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Muyskens, Jonathan B. "Tbx16 and Wnt11 coordinately regulate prechordal plate morphogenesis /." view abstract or download file of text, 2005. http://www.lib.umi.com/cr/uoregon/fullcit?p3201693.
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Thesis (Ph. D.)--University of Oregon, 2005.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 55-58). Also available for download via the World Wide Web; free to University of Oregon users.
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Burbridge, Sarah. "The role of Tbx18 in axial mesoderm development." Thesis, University of Sheffield, 2012. http://etheses.whiterose.ac.uk/3312/.
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The axial mesoderm is a specialised population of cells lying at the midline of the embryo. It is composed of two cell populations: the anterior prechordal mesoderm (PM), bounded posteriorly by the notochord (NC). A wealth of studies have shown that both PM and NC are key organising centers that pattern and regionalise the overlying neuroectoderm into fore-, mid-, hindbrain and spinal cord. However, it is unclear how the axial mesoderm becomes regionalised into PM and NC with a sharp boundary established between the two domains. Here I use the chick embryo to address this question. One of the reasons that studies into the development of axial mesoderm have been hampered is due to the lack of an exclusive marker of the PM. Here, I show that Tbx18 is a novel and exclusive marker of the PM and is expressed once the axial mesoderm has fully extended. Much emphasis has been placed in the literature upon the importance of Nodal signalling in axial mesoderm formation, however, little is known about its role in the fully extended axial mesoderm. Here, I show that Nodal initiates Tbx18 expression in the fully extended axial mesoderm, i.e. acting to further specify PM. My studies reveal, further, that Nodal signalling is inhibited by the paraxial mesoderm and retinoic acid. Together, the antagonistic signals appear to establish the posterior limit of the PM and the anterior limit of the NC. Finally, I find that Tbx18 sharpens the PM-NC boundary by downregulating the NC marker 3B9 and establishing a third subpopulation of Shh- axial mesoderm that lies at the PM-NC interface. I discuss the potential significance of this third axial mesoderm population.
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Arribas, Arranz Jéssica. "Los factores de transcripción TBX15 e YY1 en cáncer. Función y regulación de TBX15. Expresión de YY1 en cáncer de tiroides." Doctoral thesis, Universitat Autònoma de Barcelona, 2015. http://hdl.handle.net/10803/323905.
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TBX15 e YY1 son dos factores de transcripción y los factores de transcripción, como moléculas transductoras de señales, ejercen un papel clave en la regulación de muchos procesos básicos del funcionamiento y fisiología de la célula, como pueden ser la proliferación celular, la inducción de la apoptosis o la reparación del DNA. Por lo tanto, la expresión y función aberrantes de los factores de transcripción son un punto importante en la aparición y desarrollo del cáncer.
Los factores de transcripción en cáncer actúan como oncogenes o genes supresores de tumores y su expresión se encuentra alterada en muchos tipos de cáncer. En cáncer de tiroides se ha descrito la asociación de ciertos factores de transcripción específicos del tiroides con este tipo de cáncer, pero no existe información acerca de la implicación de otros factores de transcripción generales, ni tampoco sobre TBX15 e YY1. La implicación de YY1 en cáncer está documentada; sin embargo, no existen estudios relativos a la posible implicación de TBX15 en cáncer. En este contexto, la presente tesis aporta conocimiento sobre el papel del factor de transcripción TBX15 en el desarrollo del cáncer, y se analiza la expresión de YY1 en cáncer de tiroides.
Nuestro estudio describe una nueva función del factor de transcripción TBX15 como inhibidor de la apoptosis celular, lo que puede contribuir al potencial proliferativo de las células cancerígenas y sugiere a TBX15 como una diana terapéutica potencial en el tratamiento del cáncer. También, hemos demostrado que NFkB regula positivamente la transcripción de TBX15 mediante su unión a una región reguladora en la zona 5’-distal del gen TBX15. La relación entre TBX15 y NFkB puede ser importante para entender el papel de TBX15 en el cáncer.
Con referencia al factor de transcripción YY1, nuestros resultados representan el primer estudio sobre la implicación de YY1 en el cáncer de tiroides sin tener información previa sobre la expresión de este factor en este tipo cáncer. Mostramos como YY1 se encuentra sobreexpresado en cáncer diferenciado de tiroides, siendo más frecuente su expresión positiva en el tipo papilar que en el folicular, poniendo en evidencia la posible implicación de YY1 en el cáncer de tiroides.TBX15 and YY1 are transcription factors; these molecules are able to transduction signals, being essential in the regulation of many basic cellular processes including cell proliferation and apoptosis. Therefore, the anomalous expression and function of these transcription factors is crucial in the beginning and in the development of cancer. Transcription factors act as oncogenes or tumor suppressor genes and their expression is found altered in multiple types of cancer. Specific transcription factors of the thyroid gland have been reported to be associated with thyroid cancer; however there is no information about the implication of general transcription factors, such as TBX15 or YY1. The involvement of YY1 in cancer is well documented; whereas there are scarcely any studies describing the possible implication of TBX15 in cancer. In this context, the present thesis provides knowledge about the role of transcription factor TBX15 in the development of cancer; moreover, it also analyzes the expression of transcription factor YY1 in differentiated thyroid cancer. Our study reveals a novel function of transcription factor TBX15 as an inhibitor of cellular apoptosis, which can contribute to the proliferative potential of cancer cells, and may suggest TBX15 as a potential therapeutic target in cancer treatment. Furthermore, we have also proven that NFkB activates the transcription of TBX15 by binding to the 5’-flanking regulatory region of the gene TBX15. Thus, the interaction between TBX15 and NFkB could prove to be important to understand the function of TBX15 in cancer. Without any previous information regarding the expression of transcription factor YY1 in thyroid cancer, our results represent the first study about the implication of YY1 in this type of cancer. We demonstrate how YY1 is overexpressed in differentiated thyroid cancer, and what’s more, its positive expression has been found to be more frequent in the papillary type rather than in the follicular type. Therefore these results evidence the possible implication of transcription factor YY1 in thyroid cancer.
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Cinzia, Caprio. "Tbx1 functions in pharyngeal arch and cardiovascular development." Thesis, Open University, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.663223.
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Tbx 1, a gene encoding aT-box transcription factor, is required for embryonic development in humans and mice. Half dosage of this gene causes most of the features of the DiGeorge or Velocardiofacial syndrome phenotypes, including aortic arch and cardiac outflow tract abnormalities. Here we show that genetic ablation of Trp53 or pharmacological inhibition of its protein product p53 rescues almost completely aortic arch defects and significantly ameliorates outflow tract defects of Tbx1 mouse mutants. Trp53 deletion rescues the cell proliferation deficit in the second heart field of Tbx1 mutants. In addition, and surprisingly, Tbx1 and p53 proteins can be found on neighboring sites on chromatin, suggesting that they share a set of target genes. In a search for shared targets, we found that the expression of Gbx2, a gene that interacts with Tbx1 during development of the aortic arch arteries, is down regulated by Tbx1 heterozygosity and rescued by Trp53 heterozygosity. In addition, Tbx1 and p53 occupy the Gbx2 gene, indicating that both contribute to its regulation. Overall our data identify unexpected interactions between Tbx1 and Trp53 and provide a proof of principle that developmental defects associated with reduced dosage of Tbx1 can be rescued pharmacologically.
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Martin, Jody Carl. "TBx18 and the epicardium in cardiac development and regenerative medicine." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p3336705.
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Thesis (Ph. D.)--University of California, San Diego, 2008.Title from first page of PDF file (viewed January 6, 2009). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 128-139).
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De, Mesmaeker Julie Anne Laurence Nathalie. "Molecular mechanisms connecting genotype and phenotype in Tbx1 deficiency." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:56013dc6-50af-454c-b036-284e5449aa8f.
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Background: The 22q11 deletion syndrome (22q11DS), also known as DiGeorge Syndrome, affects ~1/5000 live born children. Congenital heart defects (typically outflow tract and interrupted aortic arch) are present in 75% of individuals with 22q11DS and are the major cause of mortality. Other defects are cleft palate, thymus hypoplasia, inner ear defects and neuropsychiatric abnormalities. Df(16)1 mice carry a ~1 Mb hemizygous deletion on mouse chromosome 16 in a region syntenic with 22q11 and phenocopies 22q11DS. TBX1 is a DNA-binding transcription factor located in this interval and is required for neural crest cell proliferation and migration and for cardiac development. TBX1 point mutations have been identified in patients with DiGeorge syndrome. Thus TBX1 is thought to be a major gene responsible for the cardiac phenotype in 22q11DS. A key unresolved issue is the mechanism of reduced penetrance of cardiac malformations. One possibility is environmental variation during cardiogenesis. A second possibility is that variation in the TBX1 protein interaction network results in variable penetrance of the phenotype. Mutations in TBX1 or interacting partners could affect the structure of this protein interaction network. Aim: The aim of this thesis is to characterize the molecular mechanism of TBX1 function using biochemical and genetic approaches and to define the role of environmental variation on the DiGeorge phenotype. Results First part. Interaction of Df(16)1 with high-fat maternal diet. To determine if a maternal high-fat diet affects the penetrance of cardiac and thymus malformations in the Df1 deletion mouse model, wild-type and Df1 heterozygous embryos from control and high-fat diet groups were analyzed. No significant difference in the penetrance or the severity of cardiac malformations between these groups was found. These results do not support the idea that change in the fat content of maternal diet affects phenotype in this model. Thus, it is possible that high-fat diet interacts specifically with left-right patterning rather than with the genetic control of pharyngeal arch development and neural crest cell migration and survival. Second part. George, a novel ENU induced mutation in Tbx1. The George mutation, identified and mapped to Chr16 between rs4161352 and D16Mit112, results in fully penetrant cleft palate, cardiac malformations (VSD, IAA, CAT), absent cochlea and abnormal semicircular canals, and absent thymus resembling the human DiGeorge phenotype. Tbx1 lies in this interval and sequencing identified a G > A point mutation in exon 3 which is predicted to cause a Arginine to Glutamine change at amino acid position 160. George fails to genetically complement a Tbx1 null allele, confirming that it is causative and that George is functionally a null allele. RT-PCR showed that the George mutation affects splicing, resulting in a transcript lacking exon 3. This causes the loss of 34 amino acids within the TBX1 T-box domain, thus predicting that it affects DNA binding. Transactivation assays show that while the R160Q amino acid substitution significantly reduces the transactivation capacity of TBX1, surprisingly the loss of exon 3 does not affect this function. Analysis of endogenous TBX1 in developing embryos by Western blot showed that the protein expression is absent or significantly reduced. This finding suggests that the observed George phenotype is caused primarily by a loss of TBX1 protein expression. Third part. Investigation of the protein interaction network surrounding TBX1. In order to get a better insight into the protein network surrounding TBX1, a TBX1 split renilla-luciferase protein complementation assay was set up which allowed to test the physical interaction between TBX1 and several putative interactors. It was found that GATA4, SMARCAD1, RBBP5 and PTDSR interact with wild-type TBX1 in HEK293T cells. The R160Q point mutation and the loss of exon 3 affect some of these interactions supporting the idea that variation in the protein interaction network may, at least in part, be responsible for the DGS phenotype.
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Giménez, Esteban Mariano. "Expresión y regulación De los genes WDR3 y TBX15 en cáncer." Doctoral thesis, Universitat Autònoma de Barcelona, 2012. http://hdl.handle.net/10803/121601.
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Numerosos estudios se llevan a cabo en todo el mundo para conocer las causas y el comportamiento del cáncer y aplicar este conocimiento a la mejora de la prevención, diagnóstico y tratamiento de las personas afectadas. Es en este contexto en el cual nuestro grupo pretende contribuir con estos objetivos, aportando nuevos conocimientos sobre los procesos involucrados en el desarrollo tumoral en el cáncer de tiroides en particular y en la carcinogénesis en general. El objetivo principal de este trabajo de tesis es estudiar la implicación de los genes WDR3 y TBX15 en el cáncer. El estudio de estos genes surge debido a que estudios previos llevados a cabo en nuestro laboratorio identificaron dos polimorfismos marcadores de la susceptibilidad al cáncer de tiroides en la región cromosómica 1p12, donde se encuentran estos genes. Además, esta región cromosómica ha sido asociada frecuentemente con numerosos tipos de cáncer. Uno de los polimorfismos identificados se encuentra en el intrón 24 del gen WDR3 y el otro en una región vacía de genes ubicada a 460 Kb del gen TBX15. La función de estos genes no ha sido completamente dilucidada, sin embargo, se ha propuesto que WDR3 estaría involucrado en la proliferación del ciclo celular a través de la interrupción de la biogénesis del ribosoma, además, varios estudios han mostrado una expresión irregular de las proteínas con motivos WD en determinados tipos de cáncer. Por otra parte, el gen TBX15, al igual que los demás miembros de la familia T-box, ha sido asociado a procesos del desarrollo, además, en los últimos años han surgido evidencias que indican una relación entre los genes T-box y la tumorigénesis, con efectos sobre la proliferación celular, invasión y metástasis. Es por ello que hipotetizamos que los genes WDR3 y TBX15 podrían estar relacionados con el cáncer. Numerosos estudios se llevan a cabo en nuestro laboratorio con el fin de dilucidar el papel de estos genes en la etiología del cáncer de tiroides en particular y también en el cáncer en general. En el presente trabajo de tesis realizamos un estudio de asociación de los genes WDR3 y TBX15 con la susceptibilidad al cáncer de tiroides y, seguidamente, analizamos su expresión y regulación principalmente en cáncer de tiroides y también en cáncer de colon y tumores cerebrales. El estudio de asociación del gen WDR3 con el cáncer de tiroides indica que este gen es un factor de susceptibilidad a este tipo de cáncer. Además, los análisis de expresión de WDR3 evidencian una sobre-expresión de este gen en el cáncer de tiroides y de colon. Los análisis de metilación de la región promotora de WDR3 indican que esta modificación epigenética no está involucrada en la regulación de la expresión de WDR3 a nivel transcripcional, sin embargo, el análisis de factores de transcripción de unión al promotor muestran que los factores c-Myc y CTCF actúan regulando la expresión de WDR3. Por otra parte, el estudio de asociación del gen TBX15 con el cáncer de tiroides indica que este gen no es un factor de susceptibilidad a este tipo de cáncer. Los análisis de expresión de TBX15 evidencian una expresión disminuida de este gen en el cáncer de tiroides. Los análisis de metilación de la región promotora de TBX15 en tejidos de tiroides y tejidos cerebrales, indican que esta modificación epigenética está involucrada en la regulación de la expresión de TBX15 a nivel transcripcional. El presente trabajo de tesis pone en evidencia el papel de los genes WDR3 y TBX15 en la etiología del cáncer de tiroides y sugieren su implicación en la carcinogénesis en general.There are numerous studies dedicated to find out the causes of cancer and its progression and the application of this knowledge to improving the prevention, diagnosis and treatment. In this context our group contributes to these objectives, providing new insights into the processes involved in tumor development of thyroid cancer in particular and carcinogenesis in general. The main objective of this thesis is to study the involvement of the genes WDR3 and TBX15 in cancer. The study of these genes arises from studies conducted in our laboratory that identified two polymorphisms markers of thyroid cancer susceptibility in the chromosomal region 1p12, where these genes have been mapped. Additionally, this chromosomal region has often been associated with many types of cancer. One of the polymorphisms identified is located in WDR3 (intron 24) gene and the other in a region located at 460 Kb from TBX15 gene. The function of these genes has not been completely known, however, it has been proposed that WDR3 is involved in the proliferation of the cell cycle through the disruption of the ribosome biogenesis. In addition, several studies have shown an irregular expression of WD repeat proteins in certain types of cancer. Moreover, the TBX15 gene, like other members of the T-box family, has been related to developmental processes and several evidences suggest a relationship between the T-box genes and tumorigenesis, with effects on cell proliferation, invasion and metastasis. That is why we hypothesize that genes WDR3 and TBX15 may be related to cancer. Numerous studies are conducted in our laboratory to elucidate the role of these genes in the etiology of thyroid cancer in particular and also in cancer in general. In this thesis was performed an association study of genes WDR3 and TBX15 with thyroid cancer susceptibility, and their expression and regulation were analyzed in thyroid cancer, colon cancer and brain tumors. The gene association study of WDR3 with thyroid cancer indicates that this gene is a susceptibility factor for this cancer. The expression analysis shows that the WDR3 is over-expressed in thyroid cancer and colon cancer. The methylation analysis of the promoter region of WDR3 indicates that this epigenetic modification is not involved in the regulation of WDR3 expression at transcriptional level, however, analysis of transcription factors binding to the promoter shows that the c-Myc and CTCF factors could act as regulators of the WDR3 expression. Moreover, the association study of TBX15 gene with thyroid cancer indicates that this gene is not a susceptibility factor for this cancer. The expression analysis of TBX15 shows decreased expression of this gene in thyroid cancer. The methylation analysis of the promoter region of TBX15 in thyroid tissues and brain tissues, indicates that this epigenetic modification is involved in the regulation of TBX15 expression at transcriptional level. This thesis highlights the role of genes WDR3 and TBX15 in the etiology of thyroid cancer and suggests their involvement in carcinogenesis in general.
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Briones, Leon Jose Alberto. "Investigating a Tbx1 and Pax9 genetic interaction during cardiovascular development." Thesis, University of Newcastle upon Tyne, 2015. http://hdl.handle.net/10443/2839.
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Congenital cardiovascular malformations (CCVM) are the most common type of birth defect in humans and can be life threatening for the newborn. 22q11 deletion syndrome (22q11DS) is one of the most common CCVM in humans, with patients presenting a wide variety of abnormalities including craniofacial dysmorphology, immune deficiency, mental retardation and cardiovascular defects, including ventricular septal defects, abnormal right subclavian artery and interrupted aortic arch type B. TBX1 is considered the main gene underlying the cardiovascular phenotype in 22q11DS patients, however, the great phenotypic variability among 22q11DS patients suggests genetic modifiers define the presentation of the phenotype. The transcription factor Pax9, was found significantly down-regulated in Tbx1-null embryos (a mouse model of 22q11DS). The aim of this project was to determine whether Pax9 is involved in cardiovascular development and to study a potential genetic interaction between Pax9 and Tbx1 during cardiovascular development. The results show that Pax9 is required for cardiovascular development as all Pax9-null embryos have severe cardiovascular abnormalities including IAA, VSD, BAV, DORV, and abnormal or completely absent common carotids. Furthermore, a strong genetic interaction between Pax9 and Tbx1 was found, since double heterozygosity leads to lack of formation of the 4th pharyngeal arch arteries consequently leading to a significant increase in the incidence of IAA. The molecular mechanism of this interaction between Pax9 and Tbx1 was investigated. The results show that Tbx1 does not bind to any region within the Pax9 locus in vitro and in vivo. A physical interaction between Pax9 and Tbx1 proteins was also ruled out by co-immunoprecipitation. qPCR analysis revealed a significant downregulation of Gbx2 in double heterozygous embryos, and luciferase experiments revealed Pax9 is able to promote luciferase expression of a conserved regulatory region within the Gbx2 locus, whereas Tbx1 repressed luciferase expression of this Gbx2 cloned regions. The results in this dissertation suggest Pax9 and Tbx1 regulate cardiovascular development, at least in part, through regulating Gbx2.
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Bussen, Markus. "Die funktionelle Analyse des T-box-Transkriptionsfaktors Tbx18 in der Somitogenese der Maus." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=976695405.
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Marco, Viviani de. "Estudos dos genes Tbx19 e Crhr1 em cães da raça poodle com hipercortisolismo ACTH-dependente." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-28052010-113552/.
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O hipercortisolismo ACTH-dependente (HAD), também chamado de doença de Cushing, é uma das endocrinopatias mais comumente diagnosticadas na espécie canina. A sintomatologia clínica ocorre, secundariamente, aos efeitos gliconeogênicos, catabólicos, antiinflamatórios e imunossupressores dos glicocorticóides sobre vários sistemas orgânicos. Há uma marcante predisposição da doença na raça poodle e casos familiais têm sido diagnosticados sugerindo uma causa genética. As alterações moleculares que levam ao desenvolvimento do HAD em cães permanecem indefinidas. Dentre os genes implicados no desenvolvimento dos corticotrofos e na regulação do eixo corticotrófico, destacam-se o Tbx19 e o Crhr1, respectivamente. O Tbx19 é um fator de transcrição obrigatório para a transcrição do gene da proopiomelanocortina (POMC) e para a diferenciação terminal dos corticotrofos. Como está presente, exclusivamente, em corticotrofos normais e adenomatosos, foi proposto seu envolvimento na secreção excessiva de ACTH na doença de Cushing. A presença de CRHR1 nos corticotrofinomas na espécie humana e canina levantou a hipótese da sua participação na tumorigênese hipofisária, promovendo uma estimulação celular prolongada, mesmo na ausência de hormônios hipotalâmicos. Um aumento da expressão do CRHR1 foi demonstrado nos tumores corticotróficos, apesar da secreção autônoma de ACTH e dos níveis portais suprimidos de CRH em pacientes humanos e caninos com doença de Cushing. Os objetivos do presente trabalho foram pesquisar a presença de mutações germinativas nas regiões codificadoras dos genes Tbx19 e Crhr1 em cães com HAD. Para tanto, estudamos 50 cães da raça poodle com hipercortisolismo ACTH-dependente (33 fêmeas e 17 machos), com idade média de 8,71 anos e 50 cães controle da mesma raça (32 fêmeas e 18 machos) com idade superior a 6 anos (média de 9,38 anos) e sem endocrinopatias. O DNA genômico foi extraído e amplificado através da reação de polimerização em cadeia (PCR), utilizando-se oligonucleotídeos (primers) específicos para os genes Tbx19 e Crhr1. Foi identificada uma nova variante alélica tanto no Tbx19 como no Crhr1, ambas não descritas na literatura. No gene Tbx19, a variante p. S343G foi encontrada em dois cães não aparentados, mas também em dois controles normais, sugerindo tratar-se de um novo polimorfismo. Já a variante p. V97M do Crhr1 foi encontrada, em heterozigose em um animal com HAD, porém não foi observada em cem alelos normais. O códon 97 está localizado no domínio extracelular aminoterminal do gene Crhr1, de extrema importância para a ligação com alta afinidade ao ligante. O estudo molecular da estrutura quartenária da proteína mutada, seguido da avaliação da energia de ligação da superfície de contato entre o hormônio e o receptor revelou um rearranjo estrutural com alteração da superfície de contato entre o CRH e o seu receptor CRHR1, resultando em uma energia de ligação 17% superior à do receptor selvagem. Em conclusão, esse estudo não identificou alterações no gene Tbx19 associadas ao hipercortisolismo ACTH-dependente canino, mas por outro lado, identificou pela primeira vez, uma mutação ativadora no Crhr1, provavelmente responsável pelo hipercortisolismo ACTH-dependente em um cão da raça poodle.The ACTH-dependent hypercortisolism (ADH), also called Cushing\'s disease, is one of the most commonly diagnosed endocrine diseases in dogs. The symptoms occur due to glucocorticoids excess leading to gluconeogenic, catabolic, anti-inflammatory and immunosuppressive effects in multiple organs and systems. There is a high incidence of Cushing\'s disease in Poodles and familial disease has been identified suggesting a genetic involvement. The molecular changes that lead to the development of ACTH-dependent hypercortisolism in dogs remain undefined. Among genes implicated in corticotroph development and in corticotropic axis regulation, we would like to point out Tbx19 and Crhr1, respectively. Tbx19 gene is a transcription factor required for transcription of the proopiomelanocortin gene and for terminal differentiation of the corticotroph. Inactivating mutations in that gene are associated with human isolated ACTH deficiency. Since Tbx19 is present exclusively in normal and adenomatous corticotroph cells, its involvement in the secretion of ACTH in Cushing\'s disease was proposed. The presence of CRHR1 in corticotrophinomas in humans and dogs raised the possibility of its involvement in pituitary tumorigenesis, promoting prolonged cell stimulation, even in the absence of hypothalamic hormones. An increased expression of the CRHR1 mRNA was demonstrated in human and canine ACTH-secreting pituitary adenomas, despite the autonomous ACTH secretion and the low portal levels of CRH. The aim of this study was to investigate Tbx19 and Crhr1 coding region mutations in Poodle dogs with ACTH-dependent hypercortisolism. We studied 50 Poodle dogs with ADH (33 females and 17 males) with a mean age of 8.71 years and 50 control dogs of the same breed (32 females and 18 males) older than 6 years (mean 9.38 years) and without endocrinopathies. Genomic DNA was extracted from peripheral blood, amplified by the polymerase chain reaction (PCR) using specific intronic primers and submitted to automatic sequence. We identified a new allelic variant in the Tbx19 and Crhr1 coding regions. The allelic variant p. S343G in the Tbx19 gene was found in two unrelated dogs, but also in two normal controls, suggesting that this is a new polymorphism. The Crhr1 allelic variant p. V97M was found in heterozygosity in one animal with ACTH-dependent hypercortisolism, but was not observed in one hundred normal alleles. The codon 97 is located in the extracellular amino terminal domain of the Crhr1 and is extremely important for high affinity ligand binding. The molecular analysis of the quaternary structure of normal and mutated proteins, followed by evaluation of the binding energy of the contact surface between the hormone and the receptor showed a structural rearrangement of the mutated protein by changing the contact surface between the CRH and its receptor CRHR1, resulting in a binding energy 17% higher than the wild type. In conclusion, this study did not identify Tbx19 mutations associated with canine ACTH-dependent hypercortisolism, but on the other hand, we first identified a Crhr1 gain-of-function mutation probably responsible for ACTH-dependent hypercortisolism in a Poodle dog of our cohort.
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Radosevic, Marija. "Spatial control of inner ear neurogenesis by retinoic acid, Tbx1 and her genes." Doctoral thesis, Universitat Pompeu Fabra, 2011. http://hdl.handle.net/10803/38436.
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Sensory neurons are key mediators of the transduction of external stimuli from the ear to the brain, essential for the sense of balance and hearing. Understanding when, where and how the sensory nervous system is assembled during development can provide insights on deafness and balance disorders. Here, I show in zebrafish that Her9 transcription factor is a key element in the regulation of the otic neurogenesis. Loss of Her9 function leads to the ectopic expression of neurogenic genes neurod and neurod4. Moreover, I show that Her9 acts downstream of Tbx1, and both genes are activated by retinoic acid signaling emanating from the paraxial mesoderm and negatively regulated by Hedgehog signaling. Altogether, the data demonstrates a role of retinoic acid in axial patterning and the establishment of a neurogenic domain through Tbx1 and Her9. At later stages, retinoic acid has an additional role by regulating neuronal differentiation in the statoacoustic ganglion.Les neurones sensorials de l’oïda interna són mediadores claus en la transducció dels estímuls externs des de l’oïda interna al cervell. Entendre a on, quan i com el sistema nerviós sensorial s’organitza durant el desenvolupament embrionari pot ajudar en l’estudi de les malalties neurosensorials. En el present treball, mostro en peix zebra que el factor de transcripció Her9 és un element clau en el control de la neurogènesi òtica i que Her9 es troba sota el control directe del factor Tbx1. A més, ambdos factors estan regulats de manera positva per la via de senyalització de l’àcid retinoic i negativament per la vía de hedgehog. En resum, la tesis demostra un paper de l’àcid retinoic en la regionalització axial del primordi òtic en l’eix anteroposterior i l’establiment d’un domini neurogènic a través de Tbx1 i Her9. En estadis tardans, l’àcid retinoic regula la diferenciació neuronal en el gangli estato-acústic.
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Schmidt, Martina Karin [Verfasser]. "Untersuchungen zur Funktion der Transkriptionsfaktoren Tbx18 and Uncx4.1 in der Somitogenese der Maus / Martina Karin Schmidt." Hannover : Technische Informationsbibliothek und Universitätsbibliothek Hannover (TIB), 2012. http://d-nb.info/1031334092/34.
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Bettenhausen, Eva [Verfasser]. "Functional analysis of the T-box transcription factor Tbx18 in murine urogenital system development / Eva Bettenhausen." Hannover : Technische Informationsbibliothek (TIB), 2017. http://d-nb.info/1170362583/34.
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Giuliani, Giuliano. "The role of TBX1 and OTX1 in the development of the zebrafish inner ear." Thesis, University of Sheffield, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.548543.
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Papangeli, I. "Tbx1 : potential targets and interactors relevant to development of structures affected in DiGeorge Syndrome." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/794443/.
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22q11DS is the most common microdeletion syndrome in humans, causing a range of phenotypes associated with abnormal pharyngeal development. TBX1 is considered the major genetic determinant of the syndrome. Deletion of Tbx1 in animal models phenocopies the patient manifestations. In an effort to understand the pathways involved in these processes, potential Tbx1 effectors previously determined by microarray screens were studied. Smad7 is an inhibitor of the TGF-/BMP pathways and to date several TGF-/BMP signalling genes have been described in heart development. In this thesis Smad7 was found expressed in pharyngeal and cardiovascular structures during mouse embryogenesis while a gene-trap mouse model displayed a partially penetrant 22q11DS-like phenotype. Furthermore, Tbx1 and Smad7 were found to interact synergistically towards arch artery morphogenesis. Hes1 is a transcriptional repressor, part of the Notch signalling pathway, which produces craniofacial and cardiovascular anomalies when deactivated. Expression analysis undertaken demonstrated that Hes1 overlaps with Tbx1 in the embryonic pharynx and it is diminished in Tbx1-/- embryos. A conditional mutagenesis approach revealed non cell autonomous actions for Hes1 in the ectoderm affecting great vessel and eye development, while Hes1 was required in both the ectodermal and neural crest lineages for thymus morphogenesis. Slit2 is a secreted protein that regulates axonal guidance, migration, outgrowth and branching. Recent evidence suggests a possible mechanism by which Tbx1 may regulate neural crest patterning through the Slit/Robo pathway. Slit1 and Slit2 were here shown to share expression domains with Tbx1 in the embryonic pharynx. Nevertheless, neither the Slit2 nor the Slit1;Slit2 mutation produced a 22q11DS-like phenotype while double mutation for Tbx1;Slit2 did not enhance the Tbx1 haploinsufficient phenotype. Altogether, this thesis provides data clarifying a subset of Tbx1 mechanisms important for cardiovascular development and identifies Smad7 as a Tbx1 regulated gene involved in great vessel morphogenesis.
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Jackson, Abigail. "The regulation of pharyngeal pouch morphogenesis by TBX1 and FGF signalling in the endoderm." Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/the-regulation-of-pharyngeal-pouch-morphogenesis-by-tbx1-and-fgf-signalling-in-the-endoderm(fbd54a00-52cc-4fcc-ae8e-70662a660a4c).html.
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The pharyngeal apparatus is comprised of a series of pharyngeal arches that are defined by the evagination of endodermal pouches toward the ectoderm. Whilst the transcription factor T‐box 1 (Tbx1) and the Fibroblast growth factor 8 (Fgf8) are both required for caudal pouch formation, a role for these factors in the endoderm during pouch morphogenesis has not been confirmed. The observation that Fgf8 expression is lost in Tbx1 homozygous null mutant embryos has lead to the hypothesis that FGF8 functions directly downstream of TBX1 during pouch formation. To test this hypothesis the Sox17‐2A‐icre line was used to delete Fgf8, Fibroblast growth factor receptor 1 (Fgfr1) and Fibroblast growth factor receptor 2 (Fgfr2) and Tbx1 in the endoderm, and analyse the development of the pouches and their derivatives. In all embryos with an endoderm specific deletion of Tbx1, the caudal PA remained unsegmented as caudal pouches 3 and 4 do not form. The deletion of endodermal Tbx1 severely reduced the expression of Fgf8 in the endoderm; however, the expression of Fibroblast Growth Factor (FGF) signalling readouts was maintained. All rostral and caudal pouches are present in embryos with an endoderm specific deletion of Fgf8, indicating that the loss of Fgf8 alone from this epithelium is not sufficient to disrupt the process of pouch evagination. The compound deletion of Fgfr1 and Fgfr2 from the endoderm did not prevent pouch evagination but did cause 3rd pouch hypoplasia and the rostral pouches to fuse. These data indicate that FGF signalling downstream of Fgfr1 and Fgfr2 and Tbx1 are important for pouch formation but that they are likely to function in parallel pathways within the endoderm. Further data suggests that TBX1 may be acting in an FGF independent manner to control the polarity of actin within the endodermal epithelia. Overall this data reveals that both cell signalling and actin polarity must be tightly regulated within the endoderm for the pharyngeal pouches to form correctly.
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Mehmet, Mugayer Boral. "Etablierung molekulargenetischer Methoden zur Mutationsanalyse des TBX1-Gens unter Verwendung der denaturierenden Hochdruck-Flüssigkeits-chromatographie (DHPLC)." Doctoral thesis, Universitätsbibliothek Leipzig, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-88720.
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Mit dem Ziel, die denaturierende Hochdruck-Flüssigkeitschromatographie (DHPLC) als standardisierte Methode in der molekulargenetischen Diagnostik des TBX1-Gens einzuführen, wurde an 35 Patienten mit begründetem klinischen Verdacht oder Nachweis eines congenitalen Herzfehlers die Mutationsanalyse etabliert und durchgeführt.
Die erzielten Ergebnisse bestätigten die kosteneffiziente und zugleich einfache Durchführung des Verfahrens. In der Evaluation wurde für die DHPLC zudem eine hohe Sensitivität und Spezifität nachgewiesen, womit der zukünftige Einsatz dieser Methode im routinemäßigen Mutationsscreening gerechtfertig ist. Mittels DHPLC konnten im Rahmen der vorliegenden Dissertation insgesamt 14 verschiedene Veränderungen im TBX1-Gen identifiziert und in der anschließenden Sequenzanalyse als Polymorphismen (Normvarianten) charakterisiert werden.
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Roberts, C. "The role of putative Tbx1 traget genes in the pathogenesis of the 22q11 deletion syndrome phenotype." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1390696/.
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The 22q11 deletion syndrome (22q11DS/DiGeorge Syndrome [DGS]) is a congenital disorder with complex aetiology including cardiovascular, thymic/parathyroid, craniofacial and neuro-behavioural phenotypes. These arise via abnormal development of embryonic structures including the pharyngeal arch/artery apparatus and the secondary heart field. Large (3Mb) hemizygous deletions of 22q11containing the TBX1 transcription factor are found in most human cases. Animal models and non-deleted patient data suggest haploinsufficiency of TBX1 is the major underlying cause of 22q11DS. To investigate the role of Tbx1 in cardiovascular development, putative transcriptional targets were previously identified using microarray. This thesis examines the role of two such targets, the Cyp26 gene family and Hes1. These genes are known to be involved, respectively, in the retinoic acid (RA) and Notch-signalling pathways. Both pathways are important in pharyngeal/cardiovascular development. Control of RA homeostasis/dosage is required for normal development and the Cyp26 enzymes metabolise RA to less active forms. Embryonic Cyp26 genes have altered expression in Tbx1-/-mice. This project investigated the effect of chemically blocking Cyp26 function upon pharyngeal/cardiovascular development in the chick. Furthermore, a mutant mouse model was used to establish whether loss of Cyp26b1function could result in the 22q11DS phenocopy observed. Finally, epistasis experiments ascertained whether a genetic interaction exists between Tbx1 andCyp26b1. The transcriptional repressor Hes1 is required for normal pharyngeal/cardiovascular development in the mouse. This thesis presents data showing a conserved role for her6 (zebrafish homologue) in zebrafish pharyngeal development and verification of a tbx1/her6 genetic interaction during pharyngeal development. Overall, this work provides further evidence that Tbx1 co-ordinates a number of signalling pathways in pharyngeal/cardiovascular development. This data refines the role of Tbx1 and RA-regulatory genes in 22q11DS cardiovascular phenotypes and corroborates the importance of an interaction between tbx1 and her6 (Hes1) in pharyngeal development.
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Moraes, Filipa Pontes. "Tbx1 and Bmp2 in the development of the ear, neural crest and pharyngeal system in mice." Doctoral thesis, Universidade Nova de Lisboa. Instituto de Tecnologia Química e Biológica, 2010. http://hdl.handle.net/10362/11895.
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Dissertation presented to obtain the Ph.D degree in BiologyDevelopment of the vertebrate head involves complex interactions between tissues derived from the three germ layers. Significantly, alterations in the development of this region of the embryo are often associated with a wide variety of human congenital birth defects. Some of them are inherited disorders such as Treacher Collins, Branchio-oto-renal and DiGeorge syndromes. During embryonic development, morphogenesis of the craniofacial area occurs sequentially with the formation of a variety of transient structures, which then undergo complex sequential reorganization to form the adult structures.(...)
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Choudhury, Moinuddin Hasan. "Biopacemaking : new targets and new mechanisms." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/biopacemaking-new-targets-and-new-mechanisms(b35ec222-29eb-432f-9b6d-238f3cbcd72d).html.
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Background: Biopacemaking is the attempt to replicate sinoatrial node (SAN)-like pacemaker activity in other areas of the heart by manipulating genes involved in pacemaking. Application of this could emulate the electronic pacemaker without the need for implantation of permanent hardware, or directly repair dysfunctional SAN tissue in human disease. We upregulated the transcription factors Tbx18, Tbx3 and the membrane ion exchanger NCX1 in bradycardic subsidiary atrial pacemaker (SAP) tissue which we used as a model of SAN dysfunction. We aimed to show that one or more of these gene targets could improve pacemaker function and alter the molecular character of SAP tissue and thus could potentially be used for the repair of dysfunctional SAN tissue. Methods: SAP tissue was isolated from the right atria of rats and kept beating in culture at 37°C for 48 hours. Recombinant adenoviruses were injected into SAP preparations to upregulate Tbx18, Tbx3 and NCX1 individually. Beating rate, overdrive suppression and pharmacological response to If blockade and β-adrenergic stimulation were measured along with molecular changes in pacemaker and atrial genes and proteins using RT-qPCR and immunohistochemistry. Results: Tbx18 upregulation significantly increased SAP beating rate after 48 hours of culture (a final rate of 141 ± 9 bpm in uninfected SAP tissue versus 215 ± 16 bpm in Ad-Tbx18 infected SAP tissue, p<0.01). It induced upregulation of HCN2 (p<0.01) and RYR2 (p<0.05), downregulation of HCN4 (p<0.05) and no change HCN1, Tbx3, Kv1.5, Kir2.1, Nav1.5, NCX1, Cx43, Cx45, Cav1.2 or Cav3.1. There was also no change in overdrive suppression and no change in response to pharmacology. No increase in beating rate was seen with either Tbx3 or NCX1 upregulation. Tbx3 preparations induced downregulation of the atrial genes Kir2.1 (p<0.01) and Nav1.5 (p<0.05), along with HCN1 (p<0.05), HCN4 (p<0.01), Tbx18 (p<0.05) and NCX1 (p<0.01), upregulated Cx43 (p<0.05) and showed no change in Cx45, RYR2, Kv1.5. NCX1 preparations demonstrated reduced overdrive suppression (p<0.05). Conclusion: Tbx18 showed the most potential for biopacemaking in SAP tissue, however both Tbx3 and NCX1 could be applied as secondary targets to fine tune biopacemaker function. Future work would focus on applying these targets to dysfunctional SAN tissue in larger animals.
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Lefevre, Beyer Sabrina. "Développement d'un nouvel outil génétique pour l'étude du développement du tissu conducteur ventriculaire et application à l'analyse phénotypique du mutant Tbx1, un modèle du syndrome de DiGeorge." Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM4102.
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Le système de conduction ventriculaire (SCV) est responsable de la propagation rapide de l’activité électrique dans le cœur. Il est composé du faisceau de His, des branches droite et gauche, et des fibres de Purkinje. 1) Le développement du SCV a été étudié par l’utilisation de souris transgéniques exprimant la recombinase Cre inductible, insérée par recombinaison homologue au locus du gène de la connexine-40 (Cx40). Ce gène code pour une protéine exprimée dans les trabécules ventriculaires et le SCV. La recombinaison est observée uniquement dans les cellules exprimant la Cx40 et leur descendance. Mes résultats révèlent une restriction progressive du destin des trabécules Cx40-positives en cardiomyocytes conducteurs. Les progéniteurs Cx40-positifs participent à la formation du myocarde contractile et du SCV de E10.5 à E14.5 ; alors qu’ils ne donnent que des cardiomyocytes conducteurs après E16.5. 2) L’analyse du SCV a été étudiée dans un modèle de malformation cardiaque congénitale. Le mutant Tbx1-/-, modèle du syndrome de DiGeorge humain, présente une communication inter-ventriculaire. Des défauts morphologiques du SCV sont détectés chez ces mutants : absence de branche droite et un faisceau de His moins compacté. Ceux-ci sont corrélés avec des défauts de conduction. Le phénotype observé ne résulte pas d’un défaut d’activation du programme génique à l’origine de l’établissement du SCV ; mais semble dû à la présence de la communication inter-ventriculaire qui empêcherait les cellules progénitrices du SCV de rejoindre le sommet du septum inter-ventriculaireThe ventricular conduction system (VCS) is responsible for the rapid propagation of electrical activity in the heart. The VCS is composed of the His bundle, the left and right bundle branches, and the peripheral Purkinje fibers. 1) The development of the VCS has been studied by using transgenic mice expressing the inducible Cre recombinase, introduced by homologous recombination at the locus of gene of connexin-40 (Cx40). Cx40 encodes for a protein expressing in the ventricular trabeculae and the VCS. The recombination is observed in the cells expressing Cx40 and in their descendants. My results suggest a progressive restriction of the fate of Cx40-positive trabeculae in conductive cardiomyocytes. Cx40-positive progenitors give rise to the formation of the compact myocardium and of the VCS when they are induced between E10.5-E14.5; while they participate only in the cardiomyocytes of VCS after E16.5. 2) The analysis of the VCS has been studied in a model of congenital heart malformation. The mutant Tbx1-/-, model of the DiGeorge syndrome, present a ventricular septal defect. Morphological defects of the VCS are found in Tbx1-/- hearts: an absence of right bundle branch and a non-compacted His bundle; which are correlated with functional defect. The phenotype observed in these mutants does not result from a defect of the activation in the genetic program being at the origin of the establishment in the VCS, but seems to be explain by the presence of a large ventricular septal defect, because it could block the progression of the progenitors of the VCS along the crest of the inter-ventricular septum
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Jullian, Estelle. "Myogenic fate choice in the cardiopharyngeal mesoderm." Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0363.
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Le mésoderme cardiopharyngé (CPM) est localisé au niveau crânial de l’embryon de souris, et contribue aux muscles de la tête et du cou, dérivés des arcs pharyngés, et aux cellules progénitrices du second champ cardiaque qui donne naissance au muscle cardiaque. L’étude du CPM permet de comprendre les malformations congénitales cardiaques et crâniofaciales, comme celles observées chez les patients atteints du syndrome de microdélétion 22q11.2. Chez la souris, une analyse de clonale rétrospective a établi qu’il existe une relation clonale entre certaines parties du cœur, dérivant du second champ cardiaque et certains muscles branchiomériques. Bien que, chez le protochordé Ciona, une cellule progénitrice du CPM a été identifiée, capable de contribuer au cœur et aux muscles squelettiques pharyngés, les cellules progénitrices communes entre le cœur et les muscles de la tête n’ont pas été localisées dans l’embryon de souris. L’objectif de ma thèse consiste à étudier le destin du cœur contre celui des muscles de la tête dans le CPM. Le premier chapitre des résultats adresse la localisation spatiotemporelle des potentielles cellules progénitrices bipotentes du cœur et des muscles de la tête dans le CPM murin et comment elles sont régulées. Les résultats démontrent que bien que les composants conservés soient présents, leur régulation diffère entre la souris et Ciona. Le second et le troisième chapitres de résultats présentent une analyse de l’hétérogénéité à l’intérieur du CPM et entre les arcs pharyngés. Des domains ont été déterminés dans les arcs, et le destin cellulaire reste à explorerCardiopharyngeal mesoderm is localized at the cranial level of the mouse embryo, and contributes to head and neck muscles, derived from pharyngeal arches, and cardiac muscle. Study cardiopharyngeal mesoderm allows to understand some congenital abnormalities, which have cardiac and craniofacial defects, like DiGeorge syndrome. In mouse, retrospective clonal analysis allows to determinate a relationship between second heart field and specific branchiomeric muscles. Each pharyngeal arch gives rise to a specific branchiomeric muscles group which is linked to a part of the heart. Indeed, it has been showed in Chordates, a progenitor cell which is able to contribute to the heart and head muscles. My thesis objective is to investigate heart versus head muscles fate in cardiopharyngeal mesoderm. I wanted to understand the mechanism underlying heart and head muscles specification. The first part of the thesis will undercover the localization and the timeline of the potential bipotent myogenic progenitor cells present in cardiopharyngeal mesoderm and how they are regulated. The results showed that the conserved components are present but the regulation between each component seemed to be different in the mouse compared to Ciona. The second part and the three part of the thesis will undercover the heterogeneity intra- and inter-pharyngeal arches. Domains through the core of the arches could be observed and the fate of each domain needs to be explored
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Francou, Alexandre. "Epithelial properties of Second Heart Field cardiac progenitor cells." Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM4062.
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Une partie du cœur est formée à partir des cellules progénitrices du second champ cardiaque, qui permettent une élongation rapide du tube cardiaque. Des défauts dans le développement de ces cellules entrainent des malformations cardiaques congénitales. Ces cellules sont localisées dans le péricarde dorsal au sein du mésoderme pharyngé. Mon travail de thèse a permis de démontrer pour la première fois que ces cellules sont épithéliales et polarisées, et qu’elles forment des filopodes dynamiques du côté basal. La délétion du facteur de transcription Tbx1 perturbe la polarité des cellules et la formation des filopodes, et augmente le niveau de la protéine apicale aPKCζ. Le traitement avec un activateur de aPKCζ montre le lien entre l’intégrité épithéliale, la polarité et la formation des filopodes, et l’état progéniteur des cellules. J’ai également analysé la polarité planaire dans l’épithélium, et montrais que les cellules sont anisotropiques, étirées et allongées en direction du pole artériel. Cet étirement crée une tension orientée, révélée par une accumulation polarisée d’actomyosine, jouant le rôle de rétrocontrôle négatif. En absence d‘élongation du tube cardiaque cette tension orientée est absente. Nous avons identifié une région postérieure de l’épithélium où se trouvent une tension et une prolifération élevées, ainsi qu’une forte activité YAP/TAZ qui jouerait le rôle de relai entre tension et prolifération. La tension orientée oriente les divisions cellulaires et oriente ainsi la croissance du tissu, promouvant l’addition des cellules au pole artériel. La biomécanique des cellules du second champ cardiaque semble ainsi un moteur important pour l’élongation du cœurA major part of the heart is formed by progenitor cells called the second heart field, that contribute to rapid elongation of the heart tube. Defects in second heart field development leads to congenital heart malformations. Second heart field cells are localised in pharyngeal mesoderm in the dorsal pericardial wall. This study focuses on the epithelial properties of second heart field cells and first shows that these progenitors in the dorsal pericardial wall are epithelial and polarised, and form dynamic basal filopodia. Deletion of the transcription factor Tbx1 perturbs epithelial polarity and filopodia formation and upregulates the apical determinant aPKCζ. Treatment with an activator of aPKCζ reveals that epithelial integrity, polarity and basal filopodia are coupled to the progenitor status of second heart field cells. Next we evaluated planar polarity of second heart field cells in the dorsal pericardial wall. Cells are anisotropic, being stretched and elongated on an axis directed towards the arterial pole. This stretch results in oriented epithelial tension revealed by polarised actomyosin accumulation through a negative feedback loop. In the absence of cell addition to the cardiac poles oriented tension is absent. We identified a posterior region in the epithelium with high tension, elevated proliferation and a high level of active YAP/TAZ that may act as relay between tension and proliferation. Oriented tension orients the axis of cell division and the growth of the tissue on an axis toward the arterial pole, further promoting addition of the tissue to the pole. Biomechanical feedback may thus be an important driver of heart tube elongation
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Rammah, Mayyasa. "Characterization of cardiopharyngeal progenitor cells and transcriptional regionalisation in the cardiac outflow tract." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4061.
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Le cœur des vertébrés se développe à partir du tube cardiaque et de la participation des cellules progénitrices mésodermiques du second champ cardiaque (SHF). Une perturbation de l’addition des cellules du SHF conduit à des malformations cardiaques congénitales (MCC). Chez l’embryon, l’outflow tract (OFT) dérivé du seul SHF est formé par deux domaines complémentaires qui formeront le myocarde sous-aortique et sous-pulmonaire. Ce travail analyse les cellules progénitrices du SHF qui contribuent aux deux domaines de l’OFT pour former la base de l’aorte et du tronc pulmonaire, l’identité transcriptionnelle des domaines et leur régulation. Nous avons mis en évidence une sous-population de cellules progénitrices Notch-dépendantes, situées en région antérieure du mésoderme pharyngé, qui contribue au myocarde sous-aortique. Nous avons démontré que des cascades de régulation croisées impliquant Notch/Hes1 et Tbx1/Pparg sont importantes pour former les deux domaines fonctionnels régionalisés de l’OFT. Des expériences de culture d’explants et d’embryons ont démontré que Pparg est nécessaire au déploiement des cellules du SHF et pour la régulation transcriptionnelle du futur myocarde sous-pulmonaire. Dans le domaine complémentaire, futur myocarde sous-aortique, nous avons observé l’expression de Dlk1, un régulateur négatif de Pparg. Dlk1 est en amont de la voie de régulation Notch et participe probablement à l’identité régionale de l’OFT. Dans son ensemble, ce travail identifie de nouvelles voies de signalisation et gènes qui régulent l'identité régionale du mésoderme cardio-pharyngé et de nouvelles cibles pour l’étude clinique des MCCThe vertebrate heart develops from the heart tube and the contribution of mesodermal progenitors termed second heart field (SHF). Perturbation in SHF addition leads to congenital heart defects (CHD). The outflow tract (OFT) myocardium is entirely derived from the SHF. Distinct regions of the embryonic OFT have been shown to give rise to subaortic and subpulmonary myocardium of the heart. The work described here focuses on SHF progenitor subpopulations in mouse giving rise to distinct OFT domains and characterizes the regional transcriptional identity and regulation of future subaortic and subpulmonary myocardium. We identified Notch-dependent subaortic myocardial SHF progenitors in anterior pharyngeal mesoderm. We demonstrated that Notch/Hes1 and Tbx1/Pparg cross regulatory cascades are important to establish functionally important OFT regional domains. Explant and embryo culture experiments revealed that Pparg is required for both the deployment of SHF cells and transcriptional regulation of the future subpulmonary myocardial domain. We also found that Dlk1, a negative regulator of Pparg, is expressed in the complementary subaortic domain upstream of Notch receptor activation and potentially participates in the establishment of OFT regional identity. We also report an overlapping transcriptional profile between future subaortic myocardium and subpopulation of epicardial cells at fetal stages. Finally, we provide evidence for the existence of conserved bipotential myogenic progenitors in cardiopharyngeal mesoderm coexpressing Nkx2-5 and Tbx1. Overall this work identifies novel pathways and genes in cardiopharyngeal mesoderm that may contribute to clinically relevant CHD
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Rivera, Reyes Reginaldo [Verfasser], Andreas [Akademischer Betreuer] Kispert, Thomas [Akademischer Betreuer] Thum, and Ina [Akademischer Betreuer] Gruh. "Two complementary proteomic analyses uncover new regulators of TBX18 transcriptional function / Reginaldo Rivera Reyes ; Akademische Betreuer: Andreas Kispert, Thomas Thum, Ina Gruh ; Hannover Biomedical Research School, Institut für Molekularbiologie." Hannover : Bibliothek der Medizinischen Hochschule Hannover, 2020. http://d-nb.info/1212872134/34.
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Theriault, Mylene A. "Development and Validation of Quantitative PCR Assays for DNA-Based Newborn Screening of 22q11.2 Deletion Syndrome, Spinal Muscular Atrophy, Severe Combined Immunodeficiency and Congenital Cytomegalovirus Infection." Thesis, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/30318.
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The development of new high throughput technologies able to multiplex disease biomarkers as well as advances in medical treatments has lead to the recent expansion of the newborn screening panel to include DNA-based targets. Four rare disorders; deletion 22q11.2 syndrome and Spinal Muscular Atrophy (SMA), Severe Combined Immunodeficiency (SCID) and Congenital Cytomegalovirus (CMV), are potential candidates for inclusion to the newborn screening panel within the next few years. The major focus of this study was to determine whether 5’-hydrolysis assays developed for the four distinct disorders with specific detection needs and analytical ranges could be combined on the OpenArray system and in multiplexed qPCR reactions. SNP detection of homozygous SMN1 deletions in SMA, CNV detection in the 22q11.2 critical region, and quantification of the SCID biomarker, T-cell receptor excision circles (TRECs) and CMV were all required for disease confirmation. SMA and 22q11.2 gene deletions were accurately detected using the OpenArray system, a first for the technology. The medium density deletion 22q11.2 multiplex successfully identified deletion carriers having either the larger 3 Mb deletion or the smaller 1.5 Mb deletions. Both TREC and CMV targets were detected but with a decrease in sensitivity when compared to their singleplex counterparts. Lastly, copy number detection of the TBX1 was performed when multiplexed with the TREC assay, without a decrease in detection limit of either assay. Here, we provide proof of principal that qPCR multiplexing technologies are amenable to implementation with a newborn screening laboratory.
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Wells, Simon J. "An investigation into the development and patterning of dorsal longitudinal ascending interneurons in Danio rerio." Thesis, 2011. http://hdl.handle.net/2440/71720.
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The dorsal longitudinal ascending (DoLA) interneurons are an uncommon, seemingly irregularly distributed interneuron type of the developing embryonic zebrafish spinal cord. For reasons not yet understood DoLA interneurons express tbx16, a T-box transcription factor originally recognised for its important role in mesodermal development. This is the only cell type expressing tbx16 in the developing spinal cord, making DoLA neurons one of the few neuronal types that can be identified by expression of a unique molecular marker. Throughout the natural world regularity in pattern formation is frequent; mechanisms that direct the production of regular patterns have been studied and many are well understood. The creation of irregular "patterns", especially in embryo development has been subjected to far less analysis. This is largely because studies in developmental biology frequently involve methods that disrupt regular patterning while the disruption of an irregular pattern is likely to result in similarly irregular pattern. The DoLA interneurons with their unique genetic marker offer a rare opportunity to investigate the mechanisms behind irregular patterns in development. This is of particular importance in the development of the spinal cord, as most of the known vertebrate spinal interneurons appear to have irregular distributions. The main focus of the research presented in this thesis has been to try to understand how the distribution pattern of DoLA interneurons is generated. This knowledge may then be extended to other spinal neurons and possibly to other irregular developmental patterns. In the work described in this thesis the distribution of DoLA interneurons has been extensively examined statistically. It was found that there is an underlying cryptic organisation to their peculiar distribution. This led to the surprising discovery that these neurons migrate rostrally a significant distance along the spinal cord. These neurons were also found in larval zebrafish at much older times than has previously been described, suggesting that they may play a role in post-embryonic stages. Notch signalling appears to have an influence on DoLA interneuron distribution since perturbing Presenilin (Psen) function affects the number of these cells. Interestingly, DoLA cell number is not affected when Psen1 function is inhibited but increases when Psen2 function is inhibited. Furthermore the wild type level of DoLA interneuron number can be partially rescued by inhibiting Psen1 function in combination with inhibition of Psen2 function. The creation of transgenic zebrafish lines where GFP is transcribed from tbx16 promoter sequence is described. These animals were produced to attempt to discover more about the patterning of DoLA interneurons and the function of tbx16 during development. Serendipitously, one of these transgenic lines expresses GFP in the commissural primary ascending (CoPA) interneurons. This led to the discovery that the CoPA interneurons are marked by mafba/valentino, revealing a new unique spinal neuron molecular marker.Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2011
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Farin, Henner [Verfasser]. "Function and regulation of the murine T-box genes Tbx15 and Tbx18 / von Henner Farin." 2009. http://d-nb.info/998929948/34.
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Nguyen, Thi Hoang Lan. "Essays on the Economics of Education and Market Design." Thesis, 2020. https://doi.org/10.7916/d8-gtxr-tb16.
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This dissertation consists of three essays on the economics of education and market design. The first two chapters are united in their attention on school choice issues. Chapter 1 considers a specific application, whereas chapter 2 focuses on a matching mechanism widely used in multiple applications. Both chapters 1 and 3 explore equity concerns in education but through very different lenses (affirmative action vs. educational investment) and very different settings (the United States vs. Vietnam).
Chapter 1 addresses the diversity issue that is especially prevalent in elite schools that select students based on exams. Whereas previous studies only consider the direct impact on elite schools, I quantify the effects of two widely-discussed affirmative action plans on both elite and regular schools in New York City. I find that the two plans have quite different effects. First, there is a trade-off between improving diversity and maintaining student quality in elite schools as measured by state test scores in middle school. Despite taking into account the socioeconomic status of students' neighborhoods, the Chicago plan gives rise mostly to reshuffling within elite schools. Thus, both the overall racial composition and quality of incoming students are largely preserved as in the status quo. In contrast, the Top 7% plan, which would accept into the elite sector students in the top 7% by academic performance of each public middle school, causes considerable flows of students between the elite and regular sectors. The elite sector experiences a substantial increase in the proportions of Black and Hispanic students, along with a decrease in average student quality. Analyzing the difference between the outcomes of these two policies provides some insight into how the two objectives—diversity and peer quality in elite schools—might be better balanced in general. The second difference between the plans arises because they transform the distribution of diversity across schools in different ways. The Chicago plan reduces the differences among schools within the elite sector, while the Top 7% plan reduces the gap in diversity between the two sectors even as it increases within-sector dispersion. Both plans result in considerable changes in school assignments in the regular school sector, thus affecting the average student quality in these schools.
Chapter 2, joint work with Guillaume Haeringer and Silvio Ravaioli, uses a lab experiment to study learning dynamics when participants receive feedback in centralized matching mechanisms. Our design allows for two types of learning: to coordinate within the same environment as well as to understand the underlying mechanisms. We provide additional evidence to previous work that the majority of the deviations from truth-telling, the dominant strategy in the Deferred Acceptance mechanism, are those that do not affect payoffs. Furthermore, by explicitly analyzing learning, we can confirm that at least some of the participants learn about the optimality of truth-telling, and their departures from it happen primarily when they face the same environment being repeated. Finally, we find that when learning to coordinate, agents tend to retain their previous strategy when the payoff from this strategy is high. This is suggestive evidence of reinforcement learning.
Chapter 3 documents the pattern of educational investments for high school students across different demographics and their effects on performance on the college entrance exam and in college. Survey data from Vietnam shows that high school students from higher-income households have higher education expenditure and participation in extra classes (both at the extensive and intensive margin). Minority and rural students invest less than their non-minority and urban counterparts even after controlling for income. Out of these investments, only extra classes during the school year education expenditure other than that on extra classes are effective in increasing college entrance exam scores. In terms of college performance, a higher entrance exam score leads to a slightly higher grade point average at graduation, controlling for academic department fixed effects and investments in high school. Neither education expenditure or participation in extra classes in high school show any significant effects on college performance, except that already captured in the entrance exam scores. I record multiple gender differences. Female high school students tend to receive more investments. Even though they perform slightly worse on the entrance exam than their male peers with the same investments, they perform better in college, given the same entrance exam scores.
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"Tbx18 and the epicardium in cardiac development and regenerative medicine." UNIVERSITY OF CALIFORNIA, SAN DIEGO, 2009. http://pqdtopen.proquest.com/#viewpdf?dispub=3336705.
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Bussen, Markus [Verfasser]. "Die funktionelle Analyse des T-box-Transkriptionsfaktors Tbx18 in der Somitogenese der Maus / von Markus Bussen." 2005. http://d-nb.info/976695405/34.
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Liu, Li Yang. "Association of Tissue Promoter Methylation Levels of APC, RASSF1A, CYP26A1, and TBX15 with Prostate Cancer Progression." Thesis, 2012. http://hdl.handle.net/1807/33724.
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Aberrant promoter methylation is known to silence tumor-suppressor genes in prostate cancer. Using a quantitative real-time PCR assay(MethyLight), I determined promoter methylation levels of APC, RASSF1A, CYP26A1 and TBX15 in 219 radical prostatectomies diagnosed between 1998-2001, examined their correlation with clinicopathological follow-up data including Gleason Pattern(GP), Gleason Score(GS) and pathological stage, and explored their potential in predicting biochemical recurrence(BR) using univariate and multivariate analyses.
I demonstrated that methylation status of all four genes could accurately differentiate normal from cancerous tissues. Quantitative methylation levels of APC and TBX15 correlated strongly with GP, GS, and pathological stage. Both APC and TBX15 methylation levels could significantly predict BR in univariate analysis(p-value=0.028 and 0.003, respectively). The methylation profiles of APC and TBX15 combined could discriminate patients into high, intermediate, and low risk groups of BR(p-value=0.005).
My project demonstrated that quantitative increase in promoter methylation levels of APC and TBX15 were associated with PCa progression.
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Concepcion, Daniel. "The roles of T and Tbx6 during gastrulation and determination of left/right asymmetry." Thesis, 2013. https://doi.org/10.7916/D8S75FPT.
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T and Tbx6 belong to the T-box family of transcription factors. T homozygous null mutants lack posterior somites after the seventh pair, have no distinguishable notochord, have a convoluted neural tube and die at E.10.5. In this study we investigate the phenotype of a dominant negative allele of T, TWis. Like homozygous embryos carrying the null allele of T, TWis homozygous mutants have left/right asymmetry defects. We demonstrate that left/right specific genes Cer2, Nodal, and Gdf1 are not expressed in TWis mutants and that the Notch signaling pathway, a pathway necessary for expression of left/right specific genes, is severely perturbed. We find, through the use of confocal and scanning electron microscopy, that TWis homozygous mutants have severe node morphological defects. Molecular analysis shows that TWis mutants have altered expression of the genes Shh, Foxa2 and Gsc, that not only mark structures of the midline and node, but whose expression is essential for the formation and patterning of these structures.
Tbx6 homozygous null mutants have enlarged tail buds and ectopic neural tubes in place of posterior somites. Tbx6 homozygous null mutants also have irregular development of anterior somites and left/right asymmetry defects that lead to randomization of heart looping.
In this study we made use of a microarray to find transcriptional regulators that are potentially directly regulated by Tbx6 in order to find genes that govern the establishment of presomitic mesoderm identity. Tbx6 homozygous mutant embryos were used to investigate how Tbx6 affects multiple processes in the establishment of left-right asymmetry, which include node and node cilia development and the expression of genes necessary for nodal signal transduction from the perinodal region to the left lateral plate mesoderm (LPM). We saw that the expression of transcription factors involved in node and node cilia development and genes involved in the non-canonical Wnt signaling pathway are not affected in Tbx6 homozygous mutants. We also examined whether the left-right asymmetry defects in Tbx6 homozygous mutants are due to a role for Tbx6 to directly regulate the perinodal expression of Gdf1. We show that perinodal expression of Gdf1 is lost in Tbx6 homozygous mutants at the stage in which Gdf1 is hypothesized to help shuttle Nodal from the perinodal region to the left lateral plate mesoderm. We saw that Tbx6 does not regulate expression of Gdf1 through putative binding sites located in its promoter region and did not detect a genetic interaction between the two genes in determining left/right asymmetry. Finally we saw that addition of a transgene that expresses Gdf1 in Tbx6 homozygous mutants leads to rescue of asymmetric expression of Pitx2 in the left LPM.
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Camboa, Nuno Miguel Guimarães de Sá. "A role for the Tbx18 transcription factor in the development of mesenchymal lineages through embryogenesis and adulthood." Doctoral thesis, 2013. https://repositorio-aberto.up.pt/handle/10216/75027.
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Camboa, Nuno Miguel Guimarães de Sá. "A role for the Tbx18 transcription factor in the development of mesenchymal lineages through embryogenesis and adulthood." Tese, 2013. https://repositorio-aberto.up.pt/handle/10216/75027.
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Mehmet, Mugayer Boral. "Etablierung molekulargenetischer Methoden zur Mutationsanalyse des TBX1-Gens unter Verwendung der denaturierenden Hochdruck-Flüssigkeits-chromatographie (DHPLC)." Doctoral thesis, 2011. https://ul.qucosa.de/id/qucosa%3A11425.
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Mit dem Ziel, die denaturierende Hochdruck-Flüssigkeitschromatographie (DHPLC) als standardisierte Methode in der molekulargenetischen Diagnostik des TBX1-Gens einzuführen, wurde an 35 Patienten mit begründetem klinischen Verdacht oder Nachweis eines congenitalen Herzfehlers die Mutationsanalyse etabliert und durchgeführt.
Die erzielten Ergebnisse bestätigten die kosteneffiziente und zugleich einfache Durchführung des Verfahrens. In der Evaluation wurde für die DHPLC zudem eine hohe Sensitivität und Spezifität nachgewiesen, womit der zukünftige Einsatz dieser Methode im routinemäßigen Mutationsscreening gerechtfertig ist. Mittels DHPLC konnten im Rahmen der vorliegenden Dissertation insgesamt 14 verschiedene Veränderungen im TBX1-Gen identifiziert und in der anschließenden Sequenzanalyse als Polymorphismen (Normvarianten) charakterisiert werden.
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Hami, Danyal. "Zebrafish Cardiac Development Requires a Conserved Secondary Heart Field." Diss., 2011. http://hdl.handle.net/10161/5707.
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Despite its lack of septation, the tissue patterning of the arterial pole of the zebrafish is remarkably similar to the patterning of pulmonary and aortic arterial poles observed in mouse and chick. The secondary heart field (SHF) is a conserved developmental domain in avian and mammalian embryos that contributes myocardium and smooth muscle to the cardiac arterial pole. This field is part of the overall heart field, and its myocardial component has been fate mapped from the mesoderm to the heart in both mammals and birds. In this study I demonstrate that the population that gives rise to the arterial pole of the zebrafish can be traced from the epiblast, is a discrete part of the mesodermal heart field. This zebrafish SHF contributes myocardium after initial heart tube formation, giving rise to both smooth muscle and myocardium. I show that this field expresses Isl1, a transcription factor associated with the SHF in other species. I further show that differentiation, induced by Bmp signaling, occurs in this progenitor population as cells are added to the heart tube. Some molecular pathways required for SHF development in birds and mammals are conserved in teleosts, as Nkx2.5 and Nkx2.7 as well as Fgf8 regulate Bmp signaling in the zebrafish heart fields. Additionally, the transcription factor Tbx1 and the Sonic hedgehog pathway are necessary for normal development of the zebrafish arterial pole.
Dissertation