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1
Averof, Michalis. "HOM/Hox genes of a crustacean : evolutionary implications." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.319512.
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Zhou, Bo. "Structural studies of geminin-hox and smad-hox complexes /." View abstract or full-text, 2007. http://library.ust.hk/cgi/db/thesis.pl?BICH%202007%20ZHOU.
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Svingen, Terje, and n/a. "Hox Transcription Factors: Their Involvement in Human Cancer Cells and In Vitro Functional Specificity." Griffith University. School of Biomolecular and Biomedical Science, 2005. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20050830.135356.
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Hox genes are regulatory genes encoding small proteins containing a highly conserved 61-amino acid motif, the homeodomain, that enables Hox proteins to bind to DNA at specifically recognised binding sites and transcriptionally activate their target genes. In mammalian species there are 39 Hox genes and they are structural and functional homologs of the Drosophila homeotic complex (Horn-C). During embryogenesis and early development the Hox genes are expressed in a spatiotemporal fashion, where they operate as master transcriptional regulators. Hox genes are further expressed in fully differentiated adult cells, potentially in a tissue-specific manner involving maintenance of the normal phenotype. In selected oncogenic transformations, dysregulated Hox gene expression has been observed, indicating an involvement of these transcriptional regulators in carcinogenesis and metastasis. Utilising quantitative real-time PCR assays, these studies investigated the expression patterns of 20 Hox genes and two wellcharacterised Hox cofactors (Pbx and Meis) in malignant and non-malignant human breast and skin cancer cells. Dysregulated Hox expression was observed for all malignancies tested, of which some misexpressed Hox genes seemed random, whereas other Hox transcripts showed altered levels potentially corresponding with the invasive capacity of the cells. Also, the Hox cofactors Pbx and Meis showed no marked changes in expression levels from the non-malignant to the malignant phenotypes, indicating that it is dysregulated Hox gene expression rather than dysregulated gene expression of Hox cofactors that potentially commit the cell to redifferentiate and undergo oncogenic transformation. Although the Hox proteins are known to be key transcriptional regulators of development, the mechanisms by which they gain their in vivo functional specificity is still largely unknown. They all show strikingly similar transcriptional specificity in vitro, yet show unique specificity in their in vivo environment. This paradox has been the subject of intense scrutiny, however very few direct Hox target genes have been identified, making it a difficult task to decipher the exact manner in which Hox proteins exert their functional potential. Therefore, the studies presented herein were aimed at identifying further Hox target genes in the human system. Utilising differential display approaches, several potential downstream target genes were isolated. Substantiated with real-time PCR assays, one of these potential targets was selected as a likely direct Hox gene target, and as such subjected to further studies. By the combination of bioinformatic analyses, transfection protocols and luciferase assays, a gene encoding the SR-related protein SRrpl3O was shown to be trans-activated in vitro by HOXD4 via a putative Hox binding element within its promoter region. This is the first reported link between Hox transcription factors and the SR and SR-related family of pre-mRNA splicing proteins, offering a new and exciting insight into the complex nature of Hox functional specificity. Finally, this thesis also puts forward new ideas regarding how the Hox proteins gain their transcriptional and functional specificity. Utilising bioinformatic tools in conjunction with performing an extensive review of the disparate catalogue of Hox-related research reports, work herein offers the first comprehensive analysis of the mammalian Hox gene targets in relation to their promoter structures, as well as with respect to the expanded Hox DNA-binding elements. This work reports that identified Hox targets generally contain TATA-less core promoters, many of which have several GC-box elements. The Hox binding elements show no apparent preference regarding their location relative to the transcription start site (TSS), as they are found both upstream and downstream of the TSS, as well as being located close to proximal core promoter elements for some genes and at more distant positions in other gene promoters. Finally, the core Hox binding element TAAT/ATTA contains only part of the necessary recognition sequence involved in Hox-DNA binding, and the notion that flanking base pairs dictate trans-regulatory potential is further explored with the hypothesis that the immediate 3' base pair dictates an activator/repressor-switch of the Hox trans-regulatory effect.
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Svingen, Terje. "Hox Transcription Factors: Their Involvement in Human Cancer Cells and In Vitro Functional Specificity." Thesis, Griffith University, 2005. http://hdl.handle.net/10072/365774.
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Hox genes are regulatory genes encoding small proteins containing a highly conserved 61-amino acid motif, the homeodomain, that enables Hox proteins to bind to DNA at specifically recognised binding sites and transcriptionally activate their target genes. In mammalian species there are 39 Hox genes and they are structural and functional homologs of the Drosophila homeotic complex (Horn-C). During embryogenesis and early development the Hox genes are expressed in a spatiotemporal fashion, where they operate as master transcriptional regulators. Hox genes are further expressed in fully differentiated adult cells, potentially in a tissue-specific manner involving maintenance of the normal phenotype. In selected oncogenic transformations, dysregulated Hox gene expression has been observed, indicating an involvement of these transcriptional regulators in carcinogenesis and metastasis. Utilising quantitative real-time PCR assays, these studies investigated the expression patterns of 20 Hox genes and two wellcharacterised Hox cofactors (Pbx and Meis) in malignant and non-malignant human breast and skin cancer cells. Dysregulated Hox expression was observed for all malignancies tested, of which some misexpressed Hox genes seemed random, whereas other Hox transcripts showed altered levels potentially corresponding with the invasive capacity of the cells. Also, the Hox cofactors Pbx and Meis showed no marked changes in expression levels from the non-malignant to the malignant phenotypes, indicating that it is dysregulated Hox gene expression rather than dysregulated gene expression of Hox cofactors that potentially commit the cell to redifferentiate and undergo oncogenic transformation. Although the Hox proteins are known to be key transcriptional regulators of development, the mechanisms by which they gain their in vivo functional specificity is still largely unknown. They all show strikingly similar transcriptional specificity in vitro, yet show unique specificity in their in vivo environment. This paradox has been the subject of intense scrutiny, however very few direct Hox target genes have been identified, making it a difficult task to decipher the exact manner in which Hox proteins exert their functional potential. Therefore, the studies presented herein were aimed at identifying further Hox target genes in the human system. Utilising differential display approaches, several potential downstream target genes were isolated. Substantiated with real-time PCR assays, one of these potential targets was selected as a likely direct Hox gene target, and as such subjected to further studies. By the combination of bioinformatic analyses, transfection protocols and luciferase assays, a gene encoding the SR-related protein SRrpl3O was shown to be trans-activated in vitro by HOXD4 via a putative Hox binding element within its promoter region. This is the first reported link between Hox transcription factors and the SR and SR-related family of pre-mRNA splicing proteins, offering a new and exciting insight into the complex nature of Hox functional specificity. Finally, this thesis also puts forward new ideas regarding how the Hox proteins gain their transcriptional and functional specificity. Utilising bioinformatic tools in conjunction with performing an extensive review of the disparate catalogue of Hox-related research reports, work herein offers the first comprehensive analysis of the mammalian Hox gene targets in relation to their promoter structures, as well as with respect to the expanded Hox DNA-binding elements. This work reports that identified Hox targets generally contain TATA-less core promoters, many of which have several GC-box elements. The Hox binding elements show no apparent preference regarding their location relative to the transcription start site (TSS), as they are found both upstream and downstream of the TSS, as well as being located close to proximal core promoter elements for some genes and at more distant positions in other gene promoters. Finally, the core Hox binding element TAAT/ATTA contains only part of the necessary recognition sequence involved in Hox-DNA binding, and the notion that flanking base pairs dictate trans-regulatory potential is further explored with the hypothesis that the immediate 3' base pair dictates an activator/repressor-switch of the Hox trans-regulatory effect.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
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Ackema, K. B. "Hox genes and mesenchymal stem cells." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2008.
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Smith, Margaret Louise. "An analysis of Hox genes in Myriapods." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624853.
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Plaça, Jessica Rodrigues. "Avaliação do perfil genômico dos genes da família HOX em tumores a partir de dados de bancos públicos." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/17/17154/tde-17042018-161612/.
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A família de genes HOX compreende um conjunto de fatores de transcrição altamente conservados evolutivamente. Em mamíferos, os genes HOX se subdividem em 4 clusters: HOXA, HOXB, HOXC e HOXD, atuando no desenvolvimento embrionário com a regulação de processos biológicos como proliferação, diferenciação, migração, angiogênese e apoptose que são reativados durante a carcinogênese. Estudos recentes apontam que os genes HOX podem exercer papel relevante na formação de diversos tumores sólidos, todavia ainda não foi possível caracterizar sistematicamente a expressão dos genes HOX em tumores bem como determinar seus alvos em tumores. Desta forma, o objetivo geral deste trabalho consistiu na caracterização in silico do modelo de atuação genes HOX na carcinogênese. Para cumprir este objetivo foi identificado o perfil diferencial dos genes HOX entre amostras normais e tumorais. Alvos de genes HOX foram identificados e, quando diferencialmente expressos, foram associados com os genes HOX, independentemente dos índices de metilação e CNA. Por fim, as associações finais entre os genes HOX e seus alvos foram enriquecidas com os bancos de dados KEGG e GO. Identificou-se diferentes assinaturas de expressão de genes HOX em diferentes tumores, associadas com o eixo ântero-posterior do corpo humano, bem como os folhetos embrionários originários aos tecidos tumorais, compatível com o padrão de expressão no desenvolvimento embrionário. Um número considerável de genes HOX atuam preferencialmente via enhancers na regulação de seus alvos. Como exemplo, os genes HOXB7 e HOXC11, que funcionam como moduladores anti tumorais. Finalmente, o estudo mostra que diante do número crescente de dados genômicos públicos, é possível viabilizar projetos de grande valor científico.The HOX gene family comprises a set of evolutionarily highly conserved transcription factors. In mammals, HOX genes are subdivided into four clusters: HOXA, HOXB, HOXC and HOXD, acting on the embryonic development with regulation of biological processes such as proliferation, differentiation, migration, angiogenesis and apoptosis that are reactivated during carcinogenesis. Recent studies indicate that HOX genes may play a relevant role in the formation of several solid tumors, but it has not been possible to systematically characterize the expression of HOX genes in tumors as well as to determine their targets in tumors. Thus, the general aim of this project was to characterize the in vivo model of HOX genes in carcinogenesis. To accomplish this goal the differential profile of HOX genes was identified between normal and tumor samples. HOX gene targets were identified and, when differentially expressed, were associated with HOX genes regardless of methylation and CNA indices. Finally, the final associations between the HOX genes and their targets were enriched with the KEGG and GO databases. Different signatures of HOX gene expression were identified in different tumors, associated with the anteroposterior axis of the human body, as well as the embryonic leaflets originating from the tumor tissues, compatible with the expression pattern in the embryonic development. A considerable number of HOX genes preferentially act via enhancers in the regulation of their targets. As an example, the HOXB7 and HOXC11 genes, which function as pro-tumor modulators. Finally, the study shows that in view of the growing number of public genomic data, it is possible to make feasible projects of great scientific value.
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Pearce, Jonathan J. H. "Murine chromobox genes and the maintenance of Hox gene expression patterns." Thesis, University of Cambridge, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282013.
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Lincoln, Joy. "Developmental studies of the murine homeobox gene, Hoxa-9." Thesis, Durham University, 2002. http://etheses.dur.ac.uk/4145/.
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Cell patterning during embryogenesis is essential for establishing the identity of the developing body plan. Hox genes are fundamental regulators of tissue organisation along the anterior-posterior body axis of the developing embryo. These homeodomain-containing proteins act as transcription factors during normal development. The function of the homeodomain is to bind sequence-specific DNAmotifs which allows either activation or repression of downstream effector genes, which consequently results in the control of tissue-specific determination and differentiation. Aberrant expression of such Hox genes, including Hoxa-9 can result in homeotic transformations leading to phenotypic malformations and oncogenesis. However the normal function of Hoxa-9 is poorly understood. This study explored the potential role for Hoxa-9 in normal development and differentiation. An in situ hybridisation approach was taken to define the expression of Hoxa-9 in the developing mouse. Hoxa-9 was found to expressed in a temporarily and spatially regulated manner, in particular being detected in the developing cardiac atria, ventricles and cardiac vessels during E9.5-E12 stages of development. The expression of this homeotic gene during in vitro differentiation of embryonic stem cells into cardiomyocytes and haematopoietic cells demonstrated a profile that correlated with the emergence of these cell types. The functioning relationship between Hoxa-9 expression and lineage commitment was Airther explored using over-expression in embryonic stem cells. A potential role for Hoxa-9 in normal development is discussed.
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Caronia, Giuliana. "A 147L substitution in the HOXD13 homeodomain causes a novel human limb malformation by producing a selective loss of function." Thesis, Open University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275109.
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Nagui, Refki Khalil Peter. "Hox genes and the evolution of adaptive phenotypes." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10288/document.
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Les populations sont soumises à des pressions sélectives qui agissent sur certains traits entraînant une divergence phénotypique. L'évolution des morphologies adaptatives est souvent liée avec des changements de structures préexistantes. Les insectes semi-Aquatiques ont subi une croissance de pattes exagérée qui est associée à leur adaptation et locomotion efficace à la surface de l'eau. Cette croissance excessive a facilitée l'exploitation de l'habitat aquatique restreint pour les espèces terrestres apparentées. En outre, le groupe dérivé des gerris a subi des modifications supplémentaires au niveau des pattes, de sorte que la deuxième patte (P2) est plus longue que la troisième patte (P3). Ce plan d'organisation inversé par rapport à celui des espèces terrestres, est associé à la spécialisation pour une vie sur l'eau. Les gerris ont acquis un mode de locomotion dérivée qui consiste à ramer par des mouvements simultanés de leurs P2 et des mouvements plus subtils de leurs P3 pour s'orienter. La structure et la croissance des pattes des insectes semi-Aquatiques sont réalisées durant l'embryogenèse. En effet, la nymphe qui éclot possède des pattes fonctionnelles. Il a été démontré que le facteur de transcription Hox, Ubx, est impliqué dans cette inversion du plan des pattes. Cependant, les mécanismes génétiques responsables de ces adaptations restent toujours obscurs. La thèse présentée examine ces questions à travers deux axes : premièrement, déterminer les gènes et les voies de signalisation responsables du développement et de la croissance remarquable des pattes ; deuxièmement, étudier le rôle du gène Hox impliqué dans l'inversion du plan des pattes caractéristique des gerrisPopulations are faced with selective pressures that act on certain traits resulting in phenotypic divergence. The evolution of adaptive morphological traits is often associated with changes in pre-Existing structures. In semiaquatic insects, a dramatic growth of thoracic appendages is associated with their adaptation and efficient locomotion on the water surface. This particular leg allometry facilitated the exploitation of aquatic habitats, a restricted niche for their terrestrial relatives; and hence opens a new array of ecological opportunities. Additionally, the derived group of water striders has undergone further appendage modification, such that T2-Legs are longer than T3-Legs, a ground plan associated with the specialization to open water. Water striders have evolved a derived mode of locomotion through rowing on water. They move their mid-Legs in simultaneous sweeping strokes for propulsion, and move their hind-Legs in fine movements for orientation. Leg specification and elongation in semiaquatic insects happens during early embryogenesis as the newly hatching nymphs emerge with functional legs. The Hox transcription factor Ubx was found to be implicated in the reversal in leg ground plan. Nonetheless, the genetic mechanisms underlying these leg adaptive changes are still poorly understood. The presented thesis investigates these questions through two main goals: first, to uncover the genes and pathways implicated in the development and dramatic elongation of the legs; second, to examine the dynamics of Hox control responsible for the reversal in leg ground plan characteristic of water striders
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Basford, Joshua E. "Colinear Expression of the Mouse HoxB Cluster: Potential Regulatory Role of Histone H4 Acetylation." University of Cincinnati / OhioLINK, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=ucin997988435.
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Tümpel, Stefan Wolfgang. "Transcriptional regulation of Hox genes during hindbrain development." Thesis, Open University, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424272.
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Sundaramoorthi, Hemalatha. "Identification of Hox Genes Controlling Thrombopoiesis in Zebrafish." Thesis, University of North Texas, 2015. https://digital.library.unt.edu/ark:/67531/metadc822768/.
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Thrombocytes are functional equivalents of mammalian platelets and also possess megakaryocyte features. It has been shown earlier that hox genes play a role in megakaryocyte development. Our earlier microarray analysis showed five hox genes, hoxa10b, hoxb2a, hoxc5a, hoxc11b and hoxd3a, were upregulated in zebrafish thrombocytes. However, there is no comprehensive study of genome wide scan of all the hox genes playing a role in megakaryopoiesis. I first measured the expression levels of each of these hox genes in young and mature thrombocytes and observed that all the above hox genes except hoxc11b were expressed equally in both populations of thrombocytes. hoxc11b was expressed only in young thrombocytes and not in mature thrombocytes. The goals of my study were to comprehensively knockdown hox genes and identify the specific hox genes involved in the development of thrombocytes in zebrafish. However, the existing vivo-morpholino knockdown technology was not capable of performing such genome-wide knockdowns. Therefore, I developed a novel cost- effective knockdown method by designing an antisense oligonucleotides against the target mRNA and piggybacking with standard control morpholino to silence the gene of interest. Also, to perform knockdowns of the hox genes and test for the number of thrombocytes, the available techniques were both cumbersome or required breeding and production of fish where thrombocytes are GFP labeled. Therefore, I established a flow cytometry based method of counting the number of thrombocytes. I used mepacrine to fluorescently label the blood cells and used the white cell fraction. Standard antisense oligonucleotide designed to the central portion of each of the target hox mRNAs, was piggybacked by a control morpholino and intravenously injected into the adult zebrafish. The thrombocyte count was measured 48 hours post injection. In this study, I found that the knockdown of hoxc11b resulted in increased number of thrombocytes and knockdown of hoxa10b, hoxb2a, hoxc5a, and hoxd3a showed reduction in the thrombocyte counts. I then screened the other 47 hox genes in the zebrafish genome using flow sorting method and found that knockdown of hoxa9a and hoxb1a also resulted in decreased thrombocyte number. Further, I used the dye DiI, which labels only young thrombocytes at specific concentrations and observed that the knockdown of hoxa10b, hoxb2a, hoxc5a, hoxd3a, hoxa9a and hoxb1a, lead to a decrease in young thrombocytes; whereas hoxc11b knockdown lead to increase in number of young thrombocytes. Using bromodeoxyuridine, I also showed that there is increase in release of young thrombocytes into peripheral circulation in hoxc11b knockdown fish which suggests that hoxc11b significantly promotes cell proliferation rather effecting apoptosis. In conclusion, I found six hox genes that are positive regulators and one hox gene is a negative regulator for thrombocyte development.
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Gray, Sophie. "The role of HOX genes in pancreatic cancer." Thesis, University of Surrey, 2015. http://epubs.surrey.ac.uk/807615/.
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Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of solid cancer with 5-year survival rates approaching a dismal 5%. Novel therapeutic targets need to be identified thus aiding and assisting the design of treatments which will improve survival rates that have not changed in the last 30 years. Of particular interest are homeobox (HOX) genes, a set of 39 evolutionarily conserved transcription factors involved in embryonic antero-posterior patterning. Although expressed in development, HOX genes have been found to be re-expressed and indeed dysregulated in several types of cancer including lung, breast, ovarian and renal neoplasia. Limited research has been undertaken on the dysregulation of HOX genes in PDAC. HOX genes can be antagonised using HXR9, a peptide which competitively inhibits the interaction between HOX genes and their co-factor PBX, subsequently preventing HOX genes to fulfill their role of transcription factors. Cancer-specific tumour-modelling is fundamental to drug testing. There are few animal models that recapitulate the unique tumour architecture and molecular signature of PDAC, particularly the desmoplastic reaction characteristic of this malignancy. The chorioallantoic membrane (CAM) assay, an in ovo model that utilises the immunologically naive properties of the developing chick embryo to grow a solid tumour derived from pancreatic cancer cell lines. The CAM model is not widely used in pancreatic cancer research and more work is needed to evaluate it’s efficacy for tumour remodelling and subsequent drug testing. We have found that the CAM model is suitable for drug testing as it recapitulates the architecture and molecular signature of PDAC. In order to establish the CAM model as appropriate for drug testing in this context, we assessed whether the mitogen-activated protein kinases (MAPK) pathway was conserved, due to the high frequency of mutational activation of the KRAS gene in this cancer. Global gene expression was also carried out to determine genetic changes between cells grown in vitro and cells in a tumour microenvironment in the CAM model. Experimental design We investigated whether there is a signature HOX gene profile unique to this disease. We measured HOX gene expression by RT-PCR in four well-described pancreatic cancer cell lines. HOX gene expression was also measured in commercially obtained RNA and snap-frozen pancreatic cancer tissue from surgical resections. The CAM model was set up by grafting 4 pancreatic cancer cell lines and tumour architecture and molecular signature was evaluated by H&E staining and IHC. Gene expression was assessed by microarray analysis to compare global gene expression in cell-lines and CAM tumours and conservation of mitogen-activated protein kinases (MAPK) pathway was addressed by western blotting. HOX gene expression was measured by RT-PCR in both cell lines and CAM tumours. Finally, the efficacy of HRX9 was measured by generating IC50s using MTS and LDH assays. Levels of apoptosis were measured in vitro using Annexin-V-PE assay and in vivo by cleaved-caspase activation, assessed by IHC. Results: We found that HOX gene expression was elevated in tumour samples compared with normal tissue and in particular a significantly higher expression of HOXA13 in PDAC samples compared with normal pancreas. This was confirmed at the protein level by Immunohistochemistry (IHC). We also showed that the CAM model is suitable for drug testing as it recapitulates the architecture and molecular signature of PDAC. Results showed that MAPK pathway was conserved, due to the high frequency of mutational activation of the KRAS gene in this cancer. Cleaved-caspase activation also supports the hypothesis that tumour cells are driven into apoptosis upon HXR9 treatment. Conclusions HOX gene expression is highly dys-regulated in pancreatic cancer and more work is need to individually evaluate HOX genes on interest highlighted in this study. HOX gene expression can be antagonised by using HXR9. Finally, we have demonstrated the potential for HOX gene targeting as a novel therapy for PDAC.
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De, Kumar Bony. "Induction of Hox genes and genome wide identification of Hox binding sites in mice." Thesis, Open University, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607467.
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Hox genes encode a family of transcription factors that play highly conserved regulatory roles in specifying the properties of tissues in developing embryos. Very little is known about how HOX proteins control the cellular and developmental processes governing morphogenesis through regulation of down-stream target genes. The goal of this research was to investigate on a genome-wide basis, the rules and principles which underlie the binding of different HOX proteins to target sites and understand the basis for their distinct specificities. I utilized the programmed differentiation of mouse embryonic stem cells into a neural fate with retinoids and genomic technologies to systematically investigate binding properties of two HOX proteins, HOXA1 and HOXBI and their cofactors PBX and MEIS. I analyzed the induction properties of the cells and the transcriptional dynamics and epigenetic states in Hox clusters to explore the differentiation process. An extensive and dynamic pattern of transcriptional activity indicates that Hox clusters generate a large number of non-coding RNAs which may impact their activation and chromatin states. Global identification of HOXB 1, HOXA1, PBX and MEIS binding regions by chromatin immune precipitation and high throughout sequencing (ChIP-seq) has generated insight into many potential Hox target genes. HOXA1 binding peaks generally overlapped with those of PBX and MEIS, supporting their roles as HOX co-factors. The sites bound by HOXBl uncovered new classes of binding motifs. Regulatory assays demonstrated that many of these novel motifs functioned as neuronal enhancers. Many HOXB I binding peaks have closely associated REST motifs and bind the REST repressor complex, which is important in neuronal differentiation. The close association of REST and HOXB 1 binding sites provides a mechanism for coordinating cell differentiation programs in neurogenesis. This research has uncovered novel properties of HO X proteins and their co-factors that underlie their role as master regulators of patterning and morphogenesis
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Zhang, Yunzhe. "Role of linker histone H1 in epigenetic regulation of pluripotency genes and Hox genes." Diss., Georgia Institute of Technology, 2014. http://hdl.handle.net/1853/54829.
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Linker histone H1 plays a key role in facilitating folding of higher order chromatin structure. Previous studies have shown that deletion of three somatic H1 subtypes together leads to embryonic lethality and that H1c/H1d/H1e triple knockout (TKO) embryonic stem cells (ESCs) display bulk chromatin decompaction. Following this initial work, we investigated the role of H1 and chromatin compaction in stem cell pluripotency and differentiation, as well as the regulation of Hox genes expression. We find that H1 TKO ESCs are more resistant to spontaneous differentiation, impaired in embryoid body differentiation, and largely blocked in neural differentiation. We present evidence that H1 contributes to efficient repression of the expression of pluripotency factors, Oct4 and Nanog, and participates in establishment and maintenance of DNA methylation and histone modification necessary for silencing pluripotency genes during stem cell differentiation and embryogenesis. In addition, we find reduced expression of a distinct set of Hox genes in embryos and ESCs, respectively. Furthermore, by characterizing H1c−/−; H1d−/−; and H1e−/− single-H1 null ESCs established in this study, we showed that individual H1 subtypes regulated specific Hox genes in ESCs. Finally, we demonstrate that the levels of H3K4me3 were significantly diminished at the affected Hox genes in H1 TKO- and single-H1 KO- ESCs, whereas H3K27me3 occupancy is modestly increased at specific Hox genes. Our results suggest that marked reduction of H1 levels and decondensation of bulk chromatin affect the expression of pluripotency genes and Hox genes in embryos and ESCs, which may be in part mediated through establishment and maintenance of epigenetic marks.
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Petrey, Maria Elaine. "CONSTRUCTION OF THE pC5C9LZAP VECTOR FOR ANALYSIS OF ELEMENTS RESPONSIBLE FOR SHARED AND SEPARATE REGULATION OF HOXC-8 AND HOXC-6." University of Cincinnati / OhioLINK, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=ucin997731452.
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Abdel, Samad Omar. "Hox genes and the specification of neuronal phenotype in the vertebrate hindbrain : transcriptional regulation of the Hox target gene Phox2b." Université Louis Pasteur (Strasbourg) (1971-2008), 2004. http://www.theses.fr/2004STR13027.
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Elstob, Philip Ronald. "Hox gene function and cell identity in Drosphila." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272353.
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Moreno, González Eduardo. "Characterization of the Hox patterning genes in acoel flatworms." Doctoral thesis, Universitat de Barcelona, 2010. http://hdl.handle.net/10803/1909.
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One of the main issues in animal evolution deal with the transition from radial organisms (Cnidaria and Ctnenophora), with only one axis of symmetry, the Oral-Aboral (OA) axis, to bilateral organism (Bilateria), bearing two orthogonal body axes, the Antero-posterior (AP) and the Dorso-ventral (DV) axis.Finding the extant bilateral organism closest to the bilaterian ancestor is the first and necessary step to open new ways of analysis. Recent molecular phylogenies have convincingly shown that the acoel flatworms, traditionally classified within the turbellarian Platyhelminthes, are the sister group of the remaining Bilateria, branching out before the common ancestor of protostomes, and deuterostomes.
Hox and ParaHox genes encode for transcriptional regulators involved in the control the AP body axis in all bilateral animals. Hox genes are usually organized in clusters in Bilateria, which have been originated by means of several gene tandem duplications from an original ProtoHox gene. In addition, Hox genes show a collinear correspondence between gene order within the cluster and the body levels at which these genes are expressed.
On the contrary, in the phylogenetic sister group of Bilateria, the Cnidaria, Hox genes are not linked in a single cluster and do not seem to play a similar role for patterning the OA axis.
Since it is still unclear when in the evolutionary history of bilaterians the Hox system first conferred positional identity along the AP-axis, the comparative study of the patterning genes Hox and ParaHox in acoel flatworms, could be crucial to understand the origin of the Hox-ParaHox axial patterning system and how the morphological transition from radial to bilateral animals took place.
In this Thesis, we report on the cloning, genomic arrangement, and expression domains of Hox genes in the acoel species Symsagittifera roscoffensis. Three Hox genes were detected: one from each of the major groups of Hox genes, which are anterior, central, and posterior, named SrHox1, SrHox5 and SrHoxPost respectively. All acoel species studied to date contain the same minimal complement of three Hox genes and one Cdx ParaHox gene, suggesting that the last common bilaterian ancestor (or Urbilateria) had a simple Hox gene complement, composed of only 3 or 4 genes.
In bacterial artificial chromosome cloning, sequencing, and chromosomal fluorescence in situ hybridization, Hox genes were not observed as being clustered in a unique genomic region in S. roscoffensis. Nevertheless, despite its dispersion within the genome, Hox genes are expressed in nested domains along the AP axis in the juvenile worm. The basic set of Hox genes in acoels and their coarse nested spatial deployment might be the first indicators of the role of Hox genes in the evolution of bilateral symmetry and AP positional identity from a hypothetical radial ancestor.
In order to understand how the AP axis has been established over evolutionary time, the execution of functional analyses is essential. With this purpose, we have performed the knockdown of the posterior Hox, IpHoxPost, during the postembryonic development, regeneration and adulthood of the acoel species Isodiametra pulchra, using RNA interference technologies.
The analysis has been done for the first time in acoels, and we demonstrate that the functions of this gene are restricted to the posterior region of the animal, within the muscular and neural tissues. We conclude, therefore, that the posterior Hox genes were used to specify and maintain defined anatomical regions within the AP axis of animals since the beginning of bilaterian evolution.
"Caracterización de los genes Hox en el acelo Symsagittifera roscoffensis"
TEXTO:
Los genes Hox codifican factores de transcripción que regionalizan el eje antero-posterior durante el desarrollo embrionario en todos los animales bilaterales estudiados.
Los animales radiales (cnidarios y ctenóforos) poseen genes Hox, pero estos no desempeñan un rol similar al de sus homólogos en Bilateria, por lo que el sistema de regionalización Hox puede ser considerado una innovación de los Bilateria.
Recientes análisis filogenéticos han demostrado que Acoelomorpha (acelos y nemertodermátidos), un grupo de gusanos clasificados tradicionalmente como platelmintos, divergieron antes del último antecesor común de protóstomos y deuteróstomos.
En consecuencia, representan el grupo de organismos bilaterales idóneo para estudiar la evolución del sistema Hox entre cnidarios y bilaterales. Por este motivo, el objetivo principal de esta tesis ha sido analizar el sistema Hox en acelos.
Encontramos un complemento simple de 3 genes Hox en las 2 especies de acelos estudiadas: Symsagittifera roscoffensis e Isodiametra pulchra. Estos genes no están ligados en el genoma de S. roscoffensis pero se expresan de forma colinear durante el desarrollo postembrionario, lo que representa el primer ejemplo de expresión colinear de genes Hox en Bilateria, indicando que la colinearidad estuvo presente en el ancestro de todos los Bilateria.
Las funciones del Hox posterior fueron analizadas mediante RNA de interferencia en I. pulcra. El fenotipo knockdown indica que IpHoxPost está implicado en la regulación del establecimiento de las estructuras morfológicas en la parte posterior, especialmente de los músculos bucales y los situados alrededor de los aparatos copuladores; así como en el proceso de maduración de los huevos y la proliferación celular. Esto indica que el rol del Hox posterior en la regulación del desarrollo y diversificación del mesodermo postembrionario y la musculatura ha surgido tempranamente durante la evolución de los Bilateria.
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Thorsteinsdottir, Unnur. "Functional analysis of selected Hox homeobox genes in hematopoiesis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq25175.pdf.
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Cwajna, Mark. "The sequential function of Hox genes in limb development." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=96918.
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Loss-of-function experiments have demonstrated that the establishment of the limb architecture relies upon the function of HoxA and HoxD genes, which are required from early limb bud stages onwards. While there is a tight link between Hox genes and skeletal development, Hox function during osteochondrogenesis remains unclear.Without HoxA/D genes there is an early development arrest, resulting in drastic truncation of the limb skeleton. The severity of this mutation made its analysis uninformative regarding the specific function of HoxA/D genes at later stages of limb development. In order to investigate Hox function during later stages of osteochondrogenesis, we generated conditional Hox inactivations in the osteochondrogenic lineage to circumvent the early affect of HoxA/D loss of function.Comparing the ubiquitous Hox deficiency and specific inactivation in limb skeleton progenitors suggests that HoxA/D genes are needed early on for normal bone patterning and also at later stages to support normal bone growth.Des expériences de perte de fonction ont démontré que la mise en place de l'architecture du squelette des membres requière la fonction des gènes HoxA et HoxD. Cependant, le rôle de ces gènes au cours de l'osteochondrogenèse est inconnu. Le but de mon projet de recherche était de définir ce rôle.En absence des gènes HoxA/D, le développement des membres est compromis dès les stades précoces, bien avant le début de l'osteochondrogenèse. Par conséquent, j'ai généré et analysé des inactivations conditionnelles des gènes HoxA/D dans le lignage osteochondrogenic afin d'établir le rôle de ces gènes au cours du développement osseux. Mes résultats montrent que la croissance des os en développement requiert la fonction des gènes HoxA/D dans le lignage osteochodrogénique. De plus, la comparaison entre l'inactivation ubiquitaire et conditionnelle permet de mieux comprendre la contribution précoce et tardif des gènes HoxA/D dans la formation du squelette des membres.
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Vinagre, Tânia. "Hox genes control the specification of global vertebral domains." Doctoral thesis, Universidade Nova de Lisboa, Instituto de Tecnologia Química e Biológica, 2011. http://hdl.handle.net/10362/5250.
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Dissertação apresentada para obtenção do grau de doutor em Biologia pelo Instituto de Tecnologia Química e Biológica da
Universidade Nova de LisboaThe development of an animal from embryo to adult is an actively regulated process, largely controlled through differential gene expression. Hox genes are key modulators of embryonic development. Among other functions, they are essential for patterning the body plan by conferring identity to segments along the anterior-posterior axis. In vertebrates, Hox genes can specify the identity of both individual vertebrae and global vertebral domains in the axial skeleton. Hox group 10 is responsible for the layout of the lumbar region by inhibiting rib formation, while Hox group 11 defines the sacral domain of the skeleton. It was previously thought that ribs were set out by default. Hence, it was suggested that another Hox gene would have to inhibit rib formation in the cervical domain, similarly to Hox group 10 in the caudal part of the skeleton. We produced mice bearing ribs in every vertebrae by overexpressing Hoxb6 in the PSM under the control of the Dll1 promoter, showing that the thoracic area is formed through the activity of Hox group 6 genes that specifically induce rib formation, and that the cervical domain is defined as the area that precedes Hox group 6 expression. In this study, we used our two Hox over-expression mouse models with complementary rib phenotypes to study the molecular mechanisms of rib development.(...)
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Hogvall, Mattias. "Analysis of Wnt ligands and Fz receptors in Ecdysozoa : Investigating the evolution of segmentation." Licentiate thesis, Uppsala universitet, Paleobiologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-266019.
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Goodman, Frances Rebecca. "Human malformations caused by mutations in the 5' HOX genes." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312045.
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Kaschula, Richard. "The regulation of Hox genes by microRNAs during Drosophila development." Thesis, University of Sussex, 2014. http://sro.sussex.ac.uk/id/eprint/48805/.
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Hox genes encode a family of evolutionarily conserved transcription factors involved in the activation of diverse cell differentiation programs along the antero-posterior axis of animals. Hox gene expression is controlled by a complex set of regulatory mechanisms which are still not fully understood. Despite this, misregulation of Hox gene expression can lead to severe developmental abnormalities and various forms of disease. This work addresses the way in which small non-coding RNAs (microRNAs, miRNAs) regulate Hox gene expression and function during development. To do this we use the Drosophila Hox gene Ultrabithorax (Ubx) as a paradigm for Hox gene function. Using a suite of genetic methods we first uncover a novel regulatory interaction between Drosophila Ubx and the miR-310C family of miRNAs during the development of the haltere, a small dorsal appendage involved in flight control. We also show that this miRNA cluster is required to fine tune Ubx expression. Furthermore, our data provides insight into the role played by Ubx during appendage development. Secondly, using a next generation RNA sequencing approach, we identify the full repertoire of miRNAs present in two serially homologous appendages of Drosophila – the wing and haltere. Our results show that these morphologically distinct appendages have divergent miRNA profiles, including miRNAs which display appendage-specific expression patterns. In addition, combining these profiles with available transcriptomic data enabled us to study how miRNAs are integrated into the Ubx gene regulatory networks that govern haltere development. This analysis suggests that haltere miRNAs reinforce the regulatory programmes installed by Ubx during haltere development. Our work therefore contributes to the understanding of the regulatory function of miRNAs during development and sheds light on the ways in which Hox gene expression can contribute to the formation of complex morphological structures.
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Bel-Vialar, Sophie. "Fonction des genes du groupe polycomb dans la regulation des genes hox chez la souris." Aix-Marseille 2, 1998. http://www.theses.fr/1998AIX22019.
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Nous avons etudie la fonction du gene m33, homologue fonctionnel du gene polycomb de drosophile, dans la regulation des genes hox chez la souris. Nous avons montre que l'inactivation de m33 provoque des defauts de proliferation de la plupart des populations cellulaires et des transformations homeotiques le long du squelette axial. Toutefois, l'expression spatiale des genes hox n'est pas modifiee dans des embryons m33-/-, a 12. 5 jpc. Pour verifier si la regulation des genes hox par les voies de l'acide retinoique etait changee dans les mutants m33-/-, nous avons analyse l'effet de traitements a l'acide retinoique exogene dans ces mutants, a plusieurs stades embryonnaires. Par des traitements a 7. 5 jpc, nous avons montre que m33 interagit avec les voies de regulation des genes hox par l'acide retinoique. Nous avons montre par ailleurs, que les embryons m33-/- sont sensibles a des traitements a l'acide retinoique (ra) a 6. 5 jpc et presentent des malformations squelettiques aggravees, alors que les embryons sauvages sont refractaires a des traitements au meme stade. De plus, la periode de sensibilite du gene hoxd-4 pour des traitements ra est plus precoce en absence de m33. Ces resultats suggerent que m33 controle l'accessibilite des elements de reponse a l'acide retinoique (rares). D'autre part, nous avons detecte une anteriorisation precoce du domaine d'expression du gene hoxd-11, analyse a 9. 5 jpc dans les mutants m33-/-, qui revele une avance temporelle de l'expression de ce gene. L'ensemble de ces resultats indique que m33 intervient dans l'etablissement des domaines d'expression des genes hox. Nous proposons que m33 controle l'accessibilite des elements de reponse a l'acide retinoique (rares) et qu'il est implique dans le controle de la colinearite temporelle au sein des complexes hox. Nous avons par ailleurs genere, des souris dans lesquelles deux genes du groupe pc-g, les genes bmi-1 et m33 sont inactives. Ces mutants presentent une aggravation des malformations squelettiques observees dans des mutants m33-/- et bmi-/- associe a une deregulation de certains genes hox. De plus, la severite du phenotype augmente avec le nombre de copies mutees. M33 et bmi-1 agissent donc en synergie et de facon dose dependante pour controler l'expression des genes hox.
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Ghosh, Priyanjali. "Investigating the Gene Regulatory Network Underlying Caudal Hindbrain Specification in Embryonic Zebrafish." eScholarship@UMMS, 2018. https://escholarship.umassmed.edu/gsbs_diss/979.
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To understand the gene regulatory network (GRN) governing caudal hindbrain formation in embryonic zebrafish, several early expressed factors have been manipulated, and multiple genetic mutants have been characterized. Such analyses have identified morphogens such as Retinoic Acid (RA) and Fibroblast growth factors (FGFs), as well as transcription factors like hoxb1b, hoxb1a, hnf1ba, and valentino as being required for rhombomere (r) r4-r6 formation in zebrafish. Considering that the caudal hindbrain is relatively complex – for instance, unique sets of neurons are formed in each rhombomere segment – it is likely that additional essential genes remain to be identified and integrated into the caudal hindbrain GRN.
Our results reveal that r4 gene expression is unaffected by the individual loss of hoxb1b, hoxb1a or RA, but is under the combinatorial regulation of RA together with hoxb1b. In contrast, r5/r6 gene expression is dependent on RA, FGF, hnf1ba and valentino – as individual loss of these factors abolishes r5/r6 gene expression. Analysis of six mutant lines (gas6, gbx1, sall4, eglf6, celf2, and greb1l) did not reveal rhombomere or neuronal defects, but transcriptome analysis of one line (gas6 mutant) identified expression changes for genes involved in several developmental processes – suggesting that these genes may have subtle roles in hindbrain development.
We conclude that r4-r6 formation is relatively robust, such that very few genes are absolutely required for this process. However, there are mechanistic differences in r4 versus r5/r6, such that no single factor is required for r4 development while several genes are individually required for r5/r6 formation.
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Chan, Chun-leung Sherwin, and 陳俊良. "Expression profiling and epigenetic regulation of Hox genes in cellular models of chondrogenesis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B44515534.
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Kan, Shih-hsin. "Molecular genetics of human limb malformations : hox genes and FGF pathways." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275273.
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Brooke, Nina Michelle. "The origin and evolution of hox-like genes : insights from amphioxus." Thesis, University of Reading, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287648.
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Aparicio, Samuel Alves Jana. "Studies on the Hox genes of the Japanese pufferfish, Fugu rubripes." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363343.
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Patraquim, Pedro Miguel Queirós do Patrocínio. "Molecular and developmental impact of RNA processing on mammalian Hox genes." Thesis, University of Sussex, 2016. http://sro.sussex.ac.uk/id/eprint/61484/.
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The Hox genes encode a family of evolutionarily conserved transcription factors whose differential expression along head-to-tail triggers distinct programs of cell differentiation along the body axis. Mutations affecting the expression of Hox genes disrupt normal development in animals as diverse as insects and mammals. Although the developmental, evolutionary and biomedical relevance of this gene family is indisputable, the understanding of the molecular mechanisms controlling Hox gene expression is still incomplete. In particular little is known about the ways Hox gene expression is controlled within developmental units such as the insect segments or the rhombomeres in the developing mammalian brain. Previous work in Drosophila showed that different RNA processing events including alternative transcription, alternative splicing and alternative polyadenylation can affect Hox gene expression during the development of complex tissues such as the nervous system showing that differential RNA processing contributes to the generation of elaborate Hox expression patterns in the fruitfly embryo. Here we explore the impact of RNA processing on the molecular functions and developmental expression of Hox genes in mammals. For this we apply a combination of bioinformatic and computational methods complemented by a series of experiments in mammalian cell culture. Our work shows, first, that RNA processing has a pervasive impact on the expression of murine and human Hox genes and that specific Hox RNA processing reactions are coupled to one another and have evolved in coordination with gene-duplication events. Second, we find that RNA processing affecting several independent Hox genes can lead to the generation of Hox protein isoforms that lack a DNA-binding unit (the Homeodomain) suggesting that protein isoforms that are able and unable to bind DNA might be produced during development; furthermore, experiments in cell culture suggest that shorter homeodomain-less isoforms can be generated from longer homeodomain-containing templates suggesting a novel mechanism of RNA processing predicted to substantially impact the biochemical functions of Hox proteins. Third, we find that Hox alternative polyadenylation leading to the production of different 3' untranslated regions (3' UTRs) in Hox mRNAs can explain the generation of complex spatial patterns of Hox expression in the mouse developing limbs and brain. Altogether, our work adds to the current understanding of the molecular control of Hox expression during mammalian development, showing that RNA processing can significantly impact the biochemical properties and expression of Hox proteins.
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Pettini, Tom. "The role of novel long non-coding RNAs in Hox gene regulation." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-novel-long-noncoding-rnas-in-hox-gene-regulation(c8e44900-3ac0-40be-8ec6-b50179381d17).html.
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Whole genome transcriptome analysis has revealed that a large proportion of the genome in higher metazoa is transcribed, yet only a small proportion of this transcription is protein-coding. One possible function of non-coding transcription is that it enables complex and diverse body plans to evolve through variation in deployment of a relatively common set of protein-coding genes. Functional studies suggest that long non-coding RNAs (lncRNAs) regulate gene expression via diverse mechanisms, operating in both cis and trans to activate or repress target genes. An emerging theme common to lncRNA function is interaction with proteins that modify chromatin and mediate epigenetic regulation. The Hox gene complexes are particularly rich in lncRNAs and require precise and fine-tuned expression to deploy Hox transcription factors throughout development. Here we identify and functionally characterize two novel lncRNAs within the D. melanogaster Hox complex, in the interval between Scr and Antp. We use nascent transcript fluorescent in-situ hybridization (ntFISH) to characterize the embryonic expression patterns of each lncRNA with respect to flanking Hox genes, and to analyze co-transcription within individual nuclei. We find that the transcription of one lncRNA, ncX, is an initial response to early transcription factors and may activate Scr expression, while transcription of the other lncRNA, ncPRE is consistent with activation and/or maintenance of Scr expression. ntFISH performed in D.virilis embryos revealed the presence of a lncRNA ortholog with highly similar expression to ncX, indicating functional conservation of lncRNA transcription across ~60 million years of evolution. We identify the ncPRE lncRNA locus as a binding site for multiple proteins associated with Polycomb/Trithorax response elements (PREs/TREs) and show that DNA encoding the ncPRE lncRNA functions as a bona fide PRE, mediating trans-interactions between chromosomes and silencing of nearby genes. We find that transcription through the ncPRE DNA relieves silencing, suggesting a role for endogenous transcription of the ncPRE lncRNA in relieving Polycomb-silencing and enabling Scr activation. We demonstrate that both lncRNA transcripts are required for proper Scr expression, and over-expression of either lncRNAs from ectopic genomic loci has no effect on Scr expression, but ectopic expression at the endogenous locus is associated with ectopic Scr activation, indicating that the lncRNA-mediated regulation functions locally at the site of transcription on the chromosome. ncX may mediate transvection effects previously observed at the Scr locus, independent of the protein Zeste. Together our results support a model of competing mechanisms in the regulation of Scr expression - a background of Polycomb repression acting from the ncPRE locus, which in the first thoracic segment is counteracted by lncRNA transcription and Trithorax binding to ncPRE, enabling activation and maintenance of Scr expression. This work provides a functional insight into the complex regulatory interactions between lncRNAs and epigenetic mechanisms, essential to establish and maintain the precise expression pattern of Hox genes through development.
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Weicksel, Steven E. "hox Gene Regulation and Function During Zebrafish Embryogenesis: A Dissertation." eScholarship@UMMS, 2013. https://escholarship.umassmed.edu/gsbs_diss/692.
Full textAbstract:
Hox genes encode a conserved family of homeodomain containing transcription factors essential for metazoan development. The establishment of overlapping Hox expression domains specifies tissue identities along the anterior-posterior axis during early embryogenesis and is regulated by chromatin architecture and retinoic acid (RA). Here we present the role nucleosome positioning plays in hox activation during embryogenesis. Using four stages of early embryo development, we map nucleosome positions at 37 zebrafish hox promoters. We find nucleosome arrangement to be progressive, taking place over several stages independent of RA. This progressive change in nucleosome arrangement on invariant sequence suggests that trans-factors play an important role in organizing nucleosomes. To further test the role of trans-factors, we created hoxb1b and hoxb1a mutants to determine if the loss of either protein effected nucleosome positions at the promoter of a known target, hoxb1a. Characterization of these mutations identified hindbrain segmentation defects similar to targeted deletions of mouse orthologs Hoxa1 and Hoxb1 and zebrafish hoxb1b and hoxb1a morpholino (MO) loss-of-function experiments. However, we also identified differences in hindbrain segmentation as well as phenotypes in facial motor neuron migration and reticulospinal neuron formation not previously observed in the MO experiments. Finally, we find that nucleosomes at the hoxb1a promoter are positioned differently in hoxb1b-/- embryos compared to wild-type. Together, our data provides new insight into the roles of hoxb1b and hoxb1a in zebrafish hindbrain segmentation and reticulospinal neuron formation and indicates that nucleosome positioning at hox promoters is dynamic, depending on sequence specific factors such as Hox proteins.
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Weicksel, Steven E. "hox Gene Regulation and Function During Zebrafish Embryogenesis: A Dissertation." eScholarship@UMMS, 2010. http://escholarship.umassmed.edu/gsbs_diss/692.
Full textAbstract:
Hox genes encode a conserved family of homeodomain containing transcription factors essential for metazoan development. The establishment of overlapping Hox expression domains specifies tissue identities along the anterior-posterior axis during early embryogenesis and is regulated by chromatin architecture and retinoic acid (RA). Here we present the role nucleosome positioning plays in hox activation during embryogenesis. Using four stages of early embryo development, we map nucleosome positions at 37 zebrafish hox promoters. We find nucleosome arrangement to be progressive, taking place over several stages independent of RA. This progressive change in nucleosome arrangement on invariant sequence suggests that trans-factors play an important role in organizing nucleosomes. To further test the role of trans-factors, we created hoxb1b and hoxb1a mutants to determine if the loss of either protein effected nucleosome positions at the promoter of a known target, hoxb1a. Characterization of these mutations identified hindbrain segmentation defects similar to targeted deletions of mouse orthologs Hoxa1 and Hoxb1 and zebrafish hoxb1b and hoxb1a morpholino (MO) loss-of-function experiments. However, we also identified differences in hindbrain segmentation as well as phenotypes in facial motor neuron migration and reticulospinal neuron formation not previously observed in the MO experiments. Finally, we find that nucleosomes at the hoxb1a promoter are positioned differently in hoxb1b-/- embryos compared to wild-type. Together, our data provides new insight into the roles of hoxb1b and hoxb1a in zebrafish hindbrain segmentation and reticulospinal neuron formation and indicates that nucleosome positioning at hox promoters is dynamic, depending on sequence specific factors such as Hox proteins.
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Negre, de Bofarull Bárbara. "Caracterización Genómica y Funcional de las Reorganizaciones del Complejo de Genes Hox en Drosophila." Doctoral thesis, Universitat Autònoma de Barcelona, 2005. http://hdl.handle.net/10803/3883.
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Los genes homeóticos (Hox) codifican factores de transcripción involucrados en la especificación de la identidad segmental a lo largo del eje anteroposterior en el embrión de los metazoos. Estos genes se presentan habitualmente agrupados y organizados en el mismo orden en el que se expresan a lo largo del eje anteroposterior del cuerpo. La conservación de esta organización genómica a lo largo de la filogenia ha sugerido la existencia de constricciones funcionales actuando sobre ella, pero la desestructuración del complejo en Caenorhabditis elegans y las tres roturas descritas en el género Drosophila ponen en cuestión que esta organización sea realmente necesaria para su correcto funcionamiento en algunos linajes. En este trabajo se han estudiado las consecuencias genómicas y funcionales de las dos reorganizaciones del complejo de genes Hox presentes en Drosophila buzzatii, especie perteneciente al grupo repleta. En la primera parte del trabajo se han clonado y secuenciado las regiones codificantes del gen labial (lab) en D. buzzatii y D. virilis. Se han comparado las secuencias de estas dos especies y la de D. melanogaster para comprobar si el cambio de posición del gen lab ocurrido en el linaje de D. buzzatii había producido algún cambio en la estructura del gen o en la evolución de su secuencia. Los resultados muestran una tasa de cambio heterogénea a lo largo del gen pero homogénea a lo largo de la filogenia. La tasa de cambio nucleotídico de lab se ha mantenido constante a pesar del cambio de posición. En la segunda parte del trabajo se han secuenciado dos regiones del genoma de D. buzzatii, una contiene los genes lab y abdominal A (abdA) y la otra incluye el gen proboscipedia (pb), y se ha comparado su organización génica con D. melanogaster y D. pseudoobscura para localizar con precisión los puntos de rotura. También se han comparado las secuencias no codificantes de estas regiones, se ha observado una elevada presencia de bloques conservados en los intrones y regiones adyacentes de los genes Hox. La comparación de los bloques conservados con las regiones reguladoras conocidas de los genes Hox (lab, pb y abdA) en D. melanogaster muestra que la posición y orientación de las regiones reguladoras está conservada entre las tres especies, con excepciones menores. Finalmente se analizó el patrón de expresión de los tres genes Hox en embriones y discos imaginales de D. buzzatii, D. repleta, D. virilis, y D. melanogaster, cuatro especies con diferentes organizaciones de los genes Hox. Las dos roturas estudiadas se produjeron mediante inversiones paracéntricas, con los puntos de rotura respetando las regiones reguladoras de ambos genes. De manera que las regiones reguladoras y patrones de expresión de los genes Hox adyacentes se han conservado a pesar de las reorganizaciones. En Drosophila el complejo parece tener una estructura formada por módulos (que incluyen los genes y las regiones reguladoras) independientes, cuya agrupación no es necesaria para su correcto funcionamiento. La organización de estos genes es modular y su agrupación parece ser el resultado de la inercia filogenética más que de la necesidad funcional. El descubrimiento de más reorganizaciones en otros linajes y la importancia de la colinealidad temporal en algunos organismos sugieren que la causa funcional de la conservación de la organización genómica podría ser la colinealidad temporal. Las reorganizaciones serían consecuencia de la pérdida de colinealidad temporal en organismos con desarrollo rápido por modificación de la embriogénesis.Homeotic (Hox) genes code for transcription factors involved in the specification of segmental identity in the anteroposterior axis of the early metazoan embryo. These genes are usually clustered and arranged in the same order as they are expressed along the anteroposterior body axis. The conservation of this Hox gene organization along the phylogeny has suggested the existence of functional constraints. However, the partial disassembly of the Caenorhabditis elegans complex and the three splits observed in the Drosophila genus question whether this organization is an absolute necessity for proper function in some lineages. In this work, I analysed the genomic and functional consequences of the two splits present in Drosophila buzzatii, a member of the repleta species group. In the first part, the coding regions of the labial (lab) gene were cloned in D. buzzatii and D. virilis. The sequences of these two species were compared with that of D. melanogaster to test whether the change in position of lab in de D. buzzatii lineage produced any change in gene structure or sequence evolution. The results show that the substitution rate is heterogeneous along the gene but homogeneous along the phylogeny. The nucleotide substitution rate of lab has been constant in spite of the positional change. In the second part, two regions of the D. buzzatii genome have been sequenced, one including the lab y abdominal A (abdA) genes and the other containing the proboscipedia (pb) gene, and compared with the genic organization of D. melanogaster and D. pseudoobscura to precisely locate the breakpoints. The noncoding sequences of these regions have also been compared, and a high presence of conserved blocks has been observed in the introns and surrounding regions of Hox genes. The comparison of these conserved blocks with the known regulatory regions of the Hox genes (lab, pb and abdA) in D. melanogaster shows that the position and order of the regulatory regions is conserved between the three species, with minor exceptions. Finally the expression pattern of the three Hox genes has been analysed in embryos and imaginal discs of D. buzzatii, D. repleta, D. virilis, and D. melanogaster, four species with different Hox gene arrangements. The two splits took place through two paracentric inversions, with their breakpoints between the regulatory regions of adjacent genes. So that the regulatory regions and expression patterns of these Hox genes have been conserved in spite of the reorganizations. In Drosophila the Hox gene complex seems to be composed by independent modules (including the gene and its regulatory regions), whose association is not required for proper function. The organization of these genes is modular and their clustering seems de result of phylogenetic inertia more than of functional necessity. The discovery of more rearrangements in other lineages and the significance of temporal colinearity in some organisms suggest that the functional cause of the conservation of this genomic organization would be temporal colinearity. Rearrangements would be the consequence of the loss of temporal colinearity in organisms with a very rapid mode of embriogenesis.
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Natarajan, Dipa. "Design and use of Hox-2 gene targeting constructs in murine embryonic stem cells." Thesis, University of Cambridge, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240072.
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Wang, Xing'an, and 王兴安. "Cross talk between Hox genes and sonic hedgehog signaling during mousehindbrain neurogenesis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45901041.
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Kolm, Peggy J. (Peggy Jeannette). "Patterning of the posterior neurectoderm by labial-like Hox genes and retinoids." Thesis, Massachusetts Institute of Technology, 1997. http://hdl.handle.net/1721.1/43468.
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Quigley, Hailey. "The Role of 5’ hox13 Genes in Danio rerio (Zebrafish) Caudal Fin Ray/Joint Development and Regeneration." Thesis, Université d'Ottawa / University of Ottawa, 2021. http://hdl.handle.net/10393/42027.
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Zebrafish are part of the teleost infraclass (bony fish) of the ray-finned fish. Like other teleosts, zebrafish possess the ability to regenerate most tissues, including their fins. Zebrafish fins contain segmented bony fin rays that longitudinally span the fin. The segments of fin ray are separated by fibrous joints at regularly spaced intervals providing segmentation and flexibility for the fin. Based on gene expression and changes in cell morphology, joint cell differentiation during development and regeneration proceeds through three stages: presumptive joint, joint-forming, and mature joint cells. Our lab has shown that new joint formation correlates with the upregulation of 5’ hoxa gene, hoxa13a. The hox genes encode transcription factors important for patterning in development. In mice, phenotypes resulting from loss- and gain-of-function mutations in Hox genes have revealed that the spatiotemporal expression of these genes is critical for the correct morphogenesis of the limb, a homologous structure to the fin. The first experiments in this thesis use the NTR/MTZ mechanism to partially ablate hoxa13a-expressing cells in the joints and blastema of the regenerating caudal fin. Partial ablation of the hoxa13a-expressing cells results in shorter bone segments following regeneration of the fin. This experiment draws the conclusion that hoxa13a-expressing cells are involved in the regulation of segment length. To examine the function of the 5’ hoxa/d genes in zebrafish, our lab created CRISPR/Cas9 mutations that inactivate hoxa13a, hoxa13b, and hoxd13a. The triple mutants created through serial breeding, show fin-specific defects in the formation and patterning of joints, as well as general defects in the morphology of the ray and in the actinotrichia, collagenous fibres found at the distal edge of the fin. Overall, our data suggest that hox13 genes are necessary for joint formation and proper fin ray growth. With further phenotypic and genotypic analyses our lab proposes that the dosage of hox13 alleles is responsible for anomalies in fin ray formation found in hox13 mutants.
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Reid, Alasdair Ian. "Expression and mis-expression of hox genes during morphogenesis of the chick skin." Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620553.
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Stower, Hannah Mary. "Dynamic histone modifications at the promoters of Hox genes in embryonic stem cells." Thesis, University of Birmingham, 2009. http://etheses.bham.ac.uk//id/eprint/483/.
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Histone modifications have been closely associated with changing levels of gene expression, but their role in determining, or possibly predicting, patterns of expression is uncertain. Here, the link between histone modifications and Hoxb gene expression in mouse embryonic stem (ES) cells was explored. Levels of the “active” modifications H3K9ac and H3K4me3 at Hoxb promoters varied widely from gene to gene, but were closely correlated in ES cells. Contrastingly, the repressive modification H3K27me3 was found at equivalent levels across the cluster. Treatment with the histone deacetylase inhibitor valproate induced a coordinate increase in the levels of H3K9ac and H3K4me3 at all Hoxb promoters, but not other genes, whilst H3K27me3 was unaffected. Such increases were not maintained upon removal of the inhibitor. All Hoxb genes were silent in undifferentiated ES cells, but expression was activated at defined times of differentiation in the expected 3’ to 5’ sequence. The valproate induced increase in active modifications did not induce Hoxb expression from the cluster in undifferentiated cells, nor was there any major shift in the timing of Hoxb expression in cells transiently exposed to valproate (ie. hyperacetylated) during the start of differentiation. Thus, active histone modifications at the Hox genes are uncoupled from transcription.
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de, Almeida Osório João Guilherme Patrício Picão. "Post-transcriptional regulation of Hox genes during Drosophila neural development : mechanisms and biological roles." Thesis, University of Sussex, 2015. http://sro.sussex.ac.uk/id/eprint/51613/.
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During the formation of the insect and mammalian nervous system the embryo activates specific programs of cellular differentiation along the main body axis so that the specification and organization of neural cells is set in coordination with axial level. At the genetic level such cellular specification programs rely on the regulated expression of a family of transcription factors encoded by the Hox genes. However, the precise molecular mechanisms controlling Hox expression in the nervous system are not well understood. In this thesis we investigate the molecular mechanisms underlying Hox gene expression within the Drosophila central nervous system (CNS) with a focus on post-transcriptional control via RNA binding proteins (RBP) and microRNAs (miRNAs). Much of the work is centred on the analysis of the Hox gene Ultrabithorax (Ubx) as this is the Hox gene for which post-transcriptional regulation is currently best understood. Through the combination of genetic, molecular and imaging methods we first show that the pan-neural RBP ELAV regulates Ubx RNA processing and protein expression during the embryonic development of the CNS. Secondly, using a suite of genetic and behavioural methods we report that Ubx repression by miRNAs encoded within the iab-4/iab-8 locus (miR-iab4/iab8) is required for the coordination of a specific larval behaviour: self-righting behaviour. Third, we explore the cellular basis of larval self-righting behaviour in the context of miRNA-dependent Ubx regulation and find that: (i) removal of miR-iab4/iab8 does not lead to major anatomical defects in the CNS or muscles; (ii) artificial increase in UBX protein expression in cholinergic interneurons disrupts self-righting behaviour; and (iii) UBX protein expression in cholinergic interneurons is regulated by miR-iab4/iab8. These observations imply that UBX regulation by miR-iab4/iab8 in cholinergic interneurons controls self-righting behaviour. Altogether our work adds to the current understanding of the molecular mechanisms underlying Hox gene expression during CNS formation and gives new insights on the role of RBP and miRNA regulation on the control of gene expression and behaviour.
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Chauvet, Sophie. "Fonctions des proteines hox : determinants intrinseques de specificite et genes effecteurs chez drosophila melanogaster." Aix-Marseille 2, 1999. http://www.theses.fr/1999AIX22052.
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Les genes hox, tres conserves au cours de l'evolution, specifient l'identite des differentes parties du corps. Ils codent pour des facteurs de transcription a homeodomaine (hd) et sont exprimes de facon differentielle dans l'organisme le long de l'axe antero-posterieur. Un des challenges des trente dernieres annees a ete de comprendre comment les genes hox permettent de transformer une information de position en un mouvement de morphogenese. Il est necessaire pour cela de bien connaitre l'organisation des complexes hox, la regulation de leur expression, mais surtout, de comprendre les mecanismes de leur specificite d'action in vivo et de caracteriser leurs genes cibles. Dans une partie de ce memoire, je presente l'analyse de plusieurs genes cibles potentiels chez drosophila melanogaster. Ces genes ont ete identifies a partir d'une banque enrichie en fragments d'adn genomiques associes in vivo a la proteine hox ultrabithorax qui a ete construite dans l'equipe. Plus precisement, une etude systematique des clones de cette banque a permis l'analyse de quatre genes, regules par ubx, dont les sequences ont ete conservees au cours de l'evolution, nessy, d-larp et charybde et scylla (deux genes dupliques). Le clonage de ces genes, l'etude de leur regulation et les approches pour analyser leur fonction en aval des genes hox sont decrits dans cette these. De plus, dans le cas de d-larp, nous avons aussi etudie son orthologue murin : m-larp. En effet, alors qu'une grande partie des reseaux d'interactions impliquant les genes hox a ete conservee au cours de l'evolution, on dispose de peu de donnees sur la conservation des phenomenes se produisant en aval des genes hox. Nous avons clone m-larp afin d'etudier son profil d'expression et avons ainsi montre qu'il n'avait vraisemblablement pas conserve son statut de gene cible d'hox chez mus musculus. Dans une deuxieme partie de mon travail, je me suis interessee a la question de la specificite tissulaire des proteines hox. Une meme proteine hox, exprimee dans des domaines larges et dans differents tissus, n'active en general ses genes cibles que dans une sous partie de son domaine d'expression ; ce qui peut constituer une activite tissu specifique. S'il est maintenant clairement etabli que l'information de specificite d'action des proteines hox peut etre portee non seulement par l'hd mais aussi par d'autres regions de la proteine, aucun domaine implique dans la tissu-specificite n'avait ete decrit. Dans cette deuxieme partie de mon travail, je montre que les proteines hox possedent des determinants intrinseques de specificite tissulaire, certains de ces determinants sont situes en dehors de l'hd.
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Bomtorin, Ana Durvalina. "Expressão de Ultrabithorax e o Desenvolvimento Casta-Específico de Apêndices Torácicos de Apis mellifera." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/17/17135/tde-29082013-105415/.
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A diferenciação morfo-fisiológica entre rainhas e operárias de Apis mellifera decorre da alimentação recebida durante o desenvolvimento larval. Dentre as diferenças morfológicas entre as duas castas encontram-se estruturas especializadas para a coleta de pólen e própolis, localizadas nas pernas metatorácicas das operárias, ausentes nas pernas de rainhas. Os padrões de expressão de Ultrabithorax (Ubx) durante o desenvolvimento de operárias e rainhas estão associados aos padrões de cerdas das pernas de fêmeas adultas. Pernas mesotorácicas de operárias apresentam estruturas descritas como importantes na coleta de pólen, ausentes em rainhas. Por outro lado, as asas não possuem estruturas casta-específicas. No presente trabalho, análises globais de transcrição gênica por hibridação de lâminas de microarrays a partir de RNA total de pernas metatorácicas de operárias e rainhas em três estágios do desenvolvimento mostram 1952 genes diferencialmente expressos. Discos de pernas metatorácicas de larvas no início do quinto estágio larval, quando comparados aos de estágios mais tardios no desenvolvimento, têm alto níveis de transcritos de ativadores de Ubx, o qual está 25 vezes mais expresso em estágios subseqüentes do desenvolvimento. Buscas por motivos de ligação de fatores de transcrição nos promotores dos grupos de genes diferencialmente expressos revelam que os motivos para ligação de Ubx, Zeste e Twist estão super-representados em um dos conjuntos analisados. Dentro deste grupo, estão presentes genes cujos ortólogos em Drosophila são controlados por Ubx, como o caso do gene lola. Análises do processamento do mRNA de Ubx em pernas e asas de ambas as castas mostram que são produzidas três isoformas diferentes quanto à presença de dois microéxons (m1 and m2), que contêm 42 nt and 53 nt, respectivamente. A isoforma IIa-like, que contém o m2, entretanto, parece não ser capaz de produzir uma proteína Hox, já que possui um códon de terminação antes do homeodomínio. O perfil de transcrição diferencial de Ubx entre as castas está associado a apêndices que apresentam diferenças morfológicas, sendo Ubx mais transcrito em pernas meso e metatorácicas de operárias que rainhas. Quando analisadas as porcentagens de expressão de cada isoforma nos apêndices, claramente a isoforma IVa-like, sem microéxons, é a mais transcrita em todos os tecidos. Entretanto, nota-se que nas asas anteriores, onde há menos Ubx, a isoforma IIa-like é proporcionalmente mais transcrita que II nos outros apêndices. Destaca-se uma tendência à inclusão do microéxon m1 (isoforma IIIa-like) ao mRNA de Ubx transcrito em asas posteriores e pernas de rainhas em comparação a operárias, em detrimento da isoforma IVa-like. Análises do uso da região 3UTR em pupas de operárias mostram que há um microssatélite transcrito na porção distal da região 3UTR deUbx. A estrutura secundária predita agrupa separadamente as regiões codificadora e as regiões 3UTR proximal e distal. Análises de seqüenciamento de última geração revelaram que oito dos 51 microRNAs com sítios-alvo preditos na região 3UTR de Ubx estão mais expressos em asas anteriores, e outros dois em asas posteriores. Assim, nossos resultados mostram que o controle da expressão diferencial de Ubx é dada pela ativação desse gene por fatores de transcrição que se ligam ao promotor, controle do splicing alternativo, e expressão de microRNAs diferencial em cada casta e apêndice, controlando, assim, a morfogênese diferencial dos apêndices de fêmeas observada em A. mellifera.Along with differences in physiological and behavioral characteristics, workers and queens of Apis mellifera also differ in appendage morphology. Some appendage specializations in the hind legs of honeybee workers, which are highly specialized pollinators, deserve special attention. The hind tibia of the worker has an expanded bristle-free region used for carrying pollen and propolis, the corbicula. In queens, this structure is absent. Although these morphological differences have been well characterized, the genetic inputs triggering the development of this alternative morphology have remained unknown. Through microarray analysis, we detected 1,952 genes that are differentially expressed during worker versus queen hind leg development. The gene expression signatures of the two castes have similar patterns of genes controlling development. At the beginning of the last larval instar, Ultrabithorax (Ubx) activators are more strongly expressed than in prepupae and early pupae; at this time Ubx expression is approximately 25 times higher. Within the gene expression signature, we identified a cluster formed by genes in which Ubx, Twist and Zeste binding sites are over-represented. This cluster includes genes for which Drosophila orthologs are known to be bound by Ubx, as in the case of lola. We also tested the extent of Ubx mRNA processing during wing and leg development. Unexpectedly, we found Ubx alternative splicing in both workers and queens; there were two microexons (m1 and m2) encoding 42 nt and 53 nt, respectively, arguing against the hypothesis that alternative splicing occurs exclusively within the Diptera. Inclusion of the m2 exon inserts a stop codon upstream from the exon containing the homeodomain, producing a truncated protein. Moreover, these bee microexons conserve the nucleotides known to be important for alternative splicing in Drosophila. During bee wing development, Ubx mRNA isoforms are transcribed in similar amounts in both castes; however, during leg development, queens produce 60% of the Ubx levels transcribed by workers. Analysis of 3UTR usage during bee development revealed a microsatellite region transcribed within the Ubx 3UTR. The predicted secondary structure locations separated the coding region into three branches and the proximal and the distal 3UTR regions. Deep-sequencing analysis revealed that eight out of 51 miRNAs predicted to target the Ubx mRNA are more highly expressed in worker forewings and two are more expressed in the hindwings. Therefore, we conclude that Ubx differential expression is activated by transcription factors that bind to its promoter, by control of alternative splicing, and moreover by microRNAs differentially expressed according to tissue and caste, resulting in differential morphogenesis of the hind leg in honeybee females.
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Campo-Paysaa, Florent. "Evolution du développement chez les Chordés : une histoire d'acide rétinoïque, de gènes hox et de microARNs." Thesis, Lyon, École normale supérieure, 2011. http://www.theses.fr/2011ENSL0653.
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Le but de toute étude en biologie évolutive du développement est l’étude des mécanismes développementaux à l’origine des diversifications morphologiques. Dans ce contexte, j’ai décidé de me focaliser sur l’émergence des Vertébrés au cours de l’évolution, par la mise en œuvre d’études comparatives entre différents modèles de Deutérostomiens. Le travail réalisé durant ma thèse est subdivisé en trois projets: (i) j’ai abordé le lien entre l’évolution du cerveau chez les Chordés et les modifications de la signalisation à l’acide rétinoïque (AR) au cours du développement. En particulier, j’ai examiné les rôles de l’AR au cours du développement du cerveau chez la lamproie Lampetra fluviatilis, et j’ai comparé les résultats obtenus chez cette espèce aux mécanismes développementaux agissant chez l’amphioxus, un Chordé invertébré, et chez les modèles gnathostomes classiques. Les données obtenues lors de ces analyses comparatives ont permis une meilleure compréhension de l’évolution de la régionalisation cérébrale chez les Vertébrés. (ii) j’ai étudié l’évolution des séquences régulatrices présentes au sein des clusters de gènes hox, connus pour agir dans la régionalisation du système nerveux des Chordés. L’identification d’éléments non-codants conservés ainsi que d’éléments de réponse à l’AR (RARE) potentiels dans des clusters hox de Chordés, combinée à la caractérisation de RAREs in vivo en cellules murines a permis une vision intégrée de l’évolution du contrôle des gènes hox par l’AR, chez les Chordés. (iii) j’ai analysé l’évolution des microARNs chez les Chordés en comparant les répertoires microARN chez plusieurs espèces de Deutérostomiens. Cette étude a permis d’émettre de nouvelles hypothèses quant à l’émergence des microARNs chez les animaux. Toutes ces analyses ont abordé différents aspects de l’évolution des Chordés avec pour objectif la proposition d’une vision intégrée des mécanismes moléculaires à l’origine de l’émergence des VertébrésThe aim of the evolutionary developmental biology is to study the developmental mechanisms at the base of morphological diversification. In this context, I decided to focus my attention on the emergence of vertebrates during evolution by carrying out comparative analyses in several deuterostome models. The work carried out during of my thesis can be subdivided into three major projects: (i) I addressed the link between brain evolution and modifications in retinoic acid (RA) signaling during chordate development. In particular, I investigated the roles of RA signaling in brain development in a jawless vertebrate, the lamprey Lampetra fluviatilis, and compared the results with developmental mechanisms in the invertebrate chordate amphioxus and classical developmental model systems in jawed vertebrates. Data obtained from these comparative studies provided insights into the evolution of brain patterning in vertebrate evolution. (ii) I investigated the evolution of the regulatory landscape of hox gene clusters that are known to be fundamental for the patterning of the chordate central nervous system. The identification of conserved non-coding elements and putative RA response elements (RAREs) in hox clusters of different chordate species combined with the in vivo characterization of functional RAREs in mouse F9 cells provided an integrated view of the evolution of RA-dependent hox cluster regulation in chordates. (iii) I studied the roles of microRNAs (miRNAs) in chordate evolution by comparing the miRNA complements of different deuterostome species. This analysis provided novel insights about the general mechanisms of miRNA emergence in animals and highlighted species-specific miRNA complement amplifications in different deuterostome lineages. In sum, these studies have tackled different aspects of chordate evolution from an evo-devo perspective, aiming at an integrated view of the molecular mechanisms underlying vertebrate diversification
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Moreau, Chloé. "From lateral plate mesoderm formation to limb position - Linking hox collinear activation and forelimb position in birds." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066492/document.
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La position des membres le long du corps est reproductible chez une même espèce mais est très variable entre différentes espèces. Comment les membres acquièrent leur position et quel mécanisme est à l'origine de ces variations est à ce jour non élucidé. De part leur rôle dans la mise en place des axes embryonnaires, les gènes Hox sont depuis longtemps suspectés de jouer un rôle dans ce processus. Cependant les différentes preuves disponibles à ce jour restent indirectes et corrélatives. Chez l'embryon de poulet, je montre que la position des membres est établit précocement au cours du développement, lors de la gastrulation. Je démontre que la formation de la lame latérale (i.e. le tissue d'origine des membres) est un processus graduel et que l'activation séquentielle des gènes Hox spécifie ce tissue en domaines du membre et du flanc. Dans un second temps, une combinaison d'actions activatrice et répressive des gènes Hox sur le programme d'initiation du membre, actions liées à leur organisation colinéaire, est critique pour l'organisation de la lame latérale en domaines du membre et du flanc. Enfin, en étudiant des embryons de différentes espèces d'oiseaux présentant des variations dans la longueur de leur cou et donc dans la position de leur ailes (le poulet, l'autruche et le diamant mandarin), je montre que des changements relatifs dans la séquence d'activation colinéaire des gènes Hox au cours de la gastrulation sous-tendent les variations naturelles de la position de l'aile. L'ensemble de ces résultats montre que les gènes Hox jouent un rôle direct et précoce dans le positionnement des membres et propose un model général de mise en place d'un organisme par ces gènesLimb position along the main body axis is highly consistent within one species but very variable among tetrapods. Despite major advances in our understanding of limb patterning in three dimensions, how limbs reproducibly form along the anteroposterior axis remains largely unknown. Hox genes have long been suspected to play a role in this process, however supporting evidences are mostly correlative and a direct role has yet to be demonstrated. Here, using bird embryos, I show that limb position is established very early during development, during the process of gastrulation. I find that the formation of the Lateral Plate Mesoderm (i.e. the embryonic compartment from which limbs will form) is a progressive process and that co-linear activation of Hox genes sequentially patterns it along the antero-posterior axis. Subsequent combinatorial activation and repression activities of Hox genes on limb initiation are particularly critical to pattern the LPM into limb- and non-limb-forming domains. Finally, by analyzing chicken, zebra finch and ostrich embryos which exhibit variation in their forelimb position, I show that relative changes in the timing of co-linear Hox gene activation during gastrulation underlie variation in limb position. Altogether these result shed light on the cellular and molecular mechanism that regulate limb position by showing a direct and early role for Hox genes in this process during gastrulation and provide a mechanism for variation in body plan organization observed in tetrapods
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Rottkamp, Catherine Anne-Marie. "The Role of Hox Cofactors in Vertebrate Spinal Cord Development." Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1194575822.
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