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Heß, Isabell. "Zum regulatorischen Code Chorda-spezifischer Enhancer Analyse des E1-Enhancers von sox9a und sox9b im Zebrafisch /." [S.l. : s.n.], 2007. http://nbn-resolving.de/urn:nbn:de:bsz:25-opus-43665.
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Farhat, Andalib. "Implication de la voie Prostaglandine D synthase/PGD2/SOX9 dans l'ovaire normal et pathologique et régulation par la signalisation estrogénique." Thesis, Montpellier 2, 2010. http://www.theses.fr/2010MON20206.
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L'ovaire représente à la fois un organe cible et le principal organe producteur d'estrogènes et de progestérone qui maintiennent le développement des caractères sexuels féminins et une fonction de reproduction normale. Cette production hormonale est contrôlée par les gonadotropines FSH et LH produites dans l'hypophyse, responsables dans l'ovaire de la croissance folliculaire et de l'ovulation, respectivement. Mon travail de thèse a identifié la signalisation prostaglandine D2 (PGD2), comme un nouvel élément-clé dans la signalisation des gonadotropines, contribuant à l'activation de l'expression des récepteurs FshR et LhR et des enzymes de la stéroïdogenèse SCC et StAR. La PGD2, produite dans plusieurs tissus par deux enzymes de synthèse, les prostaglandines synthases H et L-PGDS, est impliquée dans de nombreuses fonctions physiologiques et pathologiques. Comme dans l'ovaire pathologique, nous avons montré que la PGD2 avait aussi un rôle anti-prolifératif dans la cellule de granulosa de l'ovaire normal. Le cancer de l'ovaire représente la 4ème cause de mortalité par cancer chez la femme. Les mécanismes moléculaires impliqués dans le développement de ces tumeurs sont encore peu connus, bien que l'implication des estrogènes et de la Prostaglandine E2 (PGE2) dans la progression des tumeurs ovariennes épithéliales soit bien établie. D'autre part, les ovaires des souris invalidées pour les gènes codant les récepteurs aux estrogènes ou l'aromatase, possèdent des structures tubulaires contenant des cellules de Leydig et des cellules de Sertoli re-différenciées exprimant le facteur de détermination sexuelle mâle SOX9, alors qu'il n'est pas exprimé dans l'ovaire sain. Mon travail a montré que les estrogènes inhibent la transcription des gènes Sox9 et L-Pgds dans les lignées ovariennes tumorales BG1 et COV434 et que cette régulation est la résultante d'une inhibition, via le récepteur ERa et d'une activation via le récepteur ERß. Ces résultats sont en accord avec les études sur les effets prolifératifs d'ERa et le rôle anti-prolifératif d'ERß et suggèrent donc un rôle anti-prolifératif de la PGD2 dans l'ovaire tumoral et une régulation négative directe ou indirecte de l'expression de Sox9 et des Pgds par les estrogènesThe prostaglandin D2 (PGD2) pathway is involved in numerous biological processes and while it has been identified as a partner of the embryonic sex determining male cascade, the roles it plays in ovarian function remain largely unknown. PGD2 is secreted by two prostaglandin D synthases (Pgds); the male-specific lipocalin (L)-Pgds and the hematopoietic (H)-Pgds. Here, we report the localization of H-Pgds mRNA in the granulosa cells from the primary to pre-ovulatory follicles. We used adult female mice treated with HQL-79, a specific inhibitor of H-Pgds enzymatic activity, to provide evidence of an interaction between H-Pgds-produced PGD2 signaling and FSH signaling. This leads to the activation of steroidogenic Scc and StAR gene expression through increased FshR and LhR receptor expression leading to progesterone secretion. We also identify a role whereby H-Pgds-produced PGD2 is involved in the regulation of follicular growth through inhibition of granulosa cell proliferation in the growing follicles. Indeed, we report an altered H-Pgds expression in human ovarian tumors alongside a partial or complete absence of H-Pgds protein in granulosa cell tumors, suggesting a potential association between decreased levels of H-Pgds expression and a tumoral phenotype. Together, these results show PGD2 signaling to be essential for FSH action within granulosa cells, thus identifying an important and unappreciated role for PGD2 signaling in controlling the balance of proliferation, differentiation and steroidogenic activity of these cells
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Zhao, Li. "The role of Sox9 in osteogenesis." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486259.
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Bone fOlmation is an exquisitely coordinated process involving both chondrogenic and osteogenic differentiation. SOX9 is the best-known master regulator for chondrocyte differentiation and cartilage formation. Herein we demonstrate that SOX9 also participates in osteogenic differentiation;bone formation, and the action is interlocked with cAMPIPKA signaling at multilevel. Together with osteogenic markers such as Runx2, ColI a I and osteopontin, SOX9 was up-regulated in the early osteogenic stage of primary MSCs as well as in BMP-2-indued osteoblast differentiation ofC3HlOTl/2 and C2C12 cells. Overexpression of wild-type SOX9 in the progenitor cells efficiently propelled expression of multiple osteogenic marker genes such as ALP activity, type I collagen and osteocalcin expression. The promoter of the type I collagen gene was activated by SOX9. However, pathogenic mutants showed impaired osteogenesis. Furthermore, SOX9 knockdown in the bone progenitor cells inhibited osteogenic differentiation. In vivo, SOX9 overexpression in C3HIOTl12 cells slightly increased bone formation quantity, while SOX9 knockdown significantly blocked development of bone. During signaling investigation, we found the removal of PKA-phosphorylation sites of SOX9 deprived it of stimulatory effect. Chemicals specifically activating or inhibiting PKA signaling and the cognate inhibitor of PKA, PKIy, distinctly affected the SOX9 action. Fmihennore, we provide evidence that through i,ts carboxyl tenninal domain, SOX9 physically and functionally interacts with CREB, the prototypical PKA-downstream transcription factor. Thus, these results suggest that in addition to the predominate role in driving chondrogenesis, SOX9 also plays a novel role by promoting osteogenesis, which is, at both the nuclear and cytoplasmic levels, orchestrated with the PKA pathway during bone formation.
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Savov, Vasil. "The Role of SOX9 in Medulloblastoma." Doctoral thesis, Uppsala universitet, Institutionen för immunologi, genetik och patologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-274630.
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Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Overall survival is about 70% and in cases where current treatment fails, the disease recurs and most often is fatal. At the molecular level, MB can be divided into four defined subgroups: WNT, SHH, Group 3 and Group 4. Amplification of MYC family genes is common in MB and correlates with poor prognosis and tumor relapse. In this thesis we showed how MYCN initiates brain tumors when transduced in neural stem cells (NSCs). Prior to transduction, NSCs were isolated from different brain regions and at various time points. While overexpression of wild-type MYCN did not generate any tumors, orthotopic transplantation of MYCNT58A-expressing forebrain, brain stem and cerebellar NSCs induced diffuse malignant glioma, PNET-like tumors and MB, respectively. Interestingly, MYCNT58A-expressing cerebellar NSCs induced SHH-dependent MB from embryonic cells but SHH-independent MB from postnatal cells. We further showed that cerebellar NSCs transduced with both MYCNT58A and transcription factor SOX9 developed tumors faster and promoted distant migration into the forebrain. The function and regulation of SOX9 in MB cells is poorly understood. We identified SOX9 protein as target of FBW7 ubiquitin ligase and demonstrated the effects of SOX9 on MB cells migration, metastasis and drug resistance. We further blocked PI3K pathway to destabilize SOX9 which sensitized cells to cytostatic treatment. We used a (TetOFF) transgenic mouse model of MYCN-induced MB (GTML) and crossed it with a (TetON) transgene which allowed us to specifically target rare SOX9-positive cells in the tumor. In this system, MB develops spontaneously and SOX9-negative tumor cells can be killed off by doxycycline. The few remaining SOX9-positive cancer cells were able to promote distant MB recurrences. Such a pattern of relapse was recently shown for Group 3 and 4 human MB where about 90% of the recurrences were distant. In summary, this thesis demonstrates that MYCN can generate various types of brain tumors depending on the timing and location of its expression. It further defines the existence of a rare population of SOX9-expressing MB cells that are involved in causing distant MB recurrences. Finally, it describes how SOX9 is stabilized in MB cells and increases MB migration and therapy resistance.
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Hargus, Gunnar. "Die Funktion des Transkriptionsfaktors Sox9 während der Knorpelzelldifferenzierung Analyse Sox9-defizienter embryonaler Stammzellen der Maus in vitro /." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=976144824.
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Geng, Yuhong, and 耿雨紅. "Functional studies of SOX9 in mouse development." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B31243071.
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Abdel-Samad, Rana. "SOX9 et MiniSOX9 dans la tumorigenèse intestinale." Thesis, Montpellier 2, 2010. http://www.theses.fr/2010MON20068.
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SOX9 est un facteur de transcription à domaine HMG. Il est impliqué dans de multiples processus biologiques au cours du développement et de la vie adulte. En particulier, SOX9 joue un rôle important dans l'homéostasie de l'épithélium intestinal. Nous avons montré que SOX9, cible positive de la voie de signalisation oncogénique Wnt/(beta)-caténine, réprime l'expression de PKC(alpha). Cette répression implique un nouveau mécanisme d'action qui ne nécessite ni la fixation du domaine HMG à l'ADN ni le domaine de transactivation de SOX9. Nous avons également identifié MiniSOX9, un nouveau variant d'épissage de SOX9, résultant de la rétention du second intron. MiniSOX9 est fortement exprimé dans les tumeurs coliques. Il agit en tant que dominant négatif de SOX9, inhibiteur de l'expression du suppresseur de tumeurs PKC(alpha) et activateur de la voie de signalisation oncogénique Wnt/(beta)-caténine. Nos données suggèrent ainsi un rôle primordial de MiniSOX9 dans la tumorigenèse intestinale. Enfin, notre étude protéomique des partenaires de SOX9 et de MiniSOX9 permet d'ouvrir de nouvelles perspectives quant aux rôles de ces deux protéines dans l'homéostasie et la tumorigenèse intestinaleSOX9 is an HMG transcription factor involved in numerous biological processes during development and adult life. It plays an important role especially in the intestinal epithelium homeostasis. In the present study, we demonstrate that SOX9, a positive target of the oncogenic signaling pathway Wnt/(beta)-catenin, represses PKC(alpha) expression. This repression involves a new mechanism of action requiring neither HMG domain binding to DNA nor the transactivation domain of SOX9. We also report the discovery of MiniSOX9, a new SOX9 splice variant, resulting from the second intron retention. MiniSOX9 is highly expressed in colon tumors. It acts as a SOX9 dominant negative, as a repressor of the expression of the tumor suppressor PKC(alpha), and as an activator of the oncogenic signaling pathway Wnt/(beta)-catenin. Our data suggest a crucial role of MiniSOX9 in intestinal tumorigenesis. Finally, a proteomic analysis allowed us to identify potential new SOX9 and MiniSOX9 partners which will be useful to decipher the roles of these two proteins in intestinal homeostasis and tumorigenesis
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Scull, Brooks Lund P. Kay. "Intestinal regeneration after irradiation stem cells and Sox9 /." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2009. http://dc.lib.unc.edu/u?/etd,2852.
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Thesis (M.S.)--University of North Carolina at Chapel Hill, 2009.Title from electronic title page (viewed Jun. 4, 2010). "... in partial fulfillment of the requirements for the degree Master of Science in the Department of Cell and Molecular Physiology." Discipline: Cell and Molecular Physiology; Department/School: Medicine.
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Nunn, A. C. "The role of SOX9 in neural progenitor identity." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1372652/.
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Recent evidence has shown that SOX9 is required for the proliferation and multipotentiality of neural progenitors in the developing CNS. Notably, these findings suggest that in contrast to previous studies, SOX9 is important for differentiation along the neuronal lineage, both in the adult and embryonic CNS. Here, a phenotypic analysis of the CNS-specific Sox9-null forebrain, including detailed analysis of cortical lamination, shows that neurons of the appropriate layer-identity are born and migrate to their destined layers. All other parameters in this analysis were normal, with the exception of the formation of glia from the ventral and dorsal telencephalons, and midline glial structures, which were absent in the mutant. Since Sox9 is expressed long before the onset of gliogenesis in these brain regions, the possibility that Sox9 may ‘prime’ the progenitors of the ventricular zone to respond to a gliogenic signal arose. To investigate this, populations of Sox9-deficient and wild-type dorsal telencephalon cells were enriched for progenitors and subjected to transcriptional profiling. Bioinformatic analysis revealed that ‘vascular endothelial growth factor’ receptors, which are important for gliogenesis, were down-regulated, in addition to two transcription factors. Previously, Sox9-deficient neural progenitors have been shown to generate neurospheres poorly, and so the dataset of potential targets was used to identify candidates that might mediate this reduced neurosphere-forming ability. Thirteen down-regulated targets were confirmed by qPCR, six of which were expressed in the same distribution as Sox9 in the embryonic telencephalon; three were also expressed in neurosphere cultures. Of these, one encoded a K+ channel (Kir4.1), and the other a modulator of the GABAA channel (DBI). In order to show that reduced expression of one of these might contribute to the Sox9-deficient neurosphere phenotype, pharmacological modulators were used and showed that blockade of Kir4.1 or enhancement of GABAA channels mimicked the effect of Sox9 loss, leaving open the possibility that Kir4.1 or DBI expression might mediate this effect.
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Roberts, Neil Alistair. "The role of SOX9 during human pancreas development." Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-sox9-during-human-pancreas-development(dab5d8da-4c02-4592-b05e-471984461dcc).html.
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The work presented in this thesis is a study of human pancreas development. The principle goal of this work is to provide information that can be used in the development of treatments for Type 1 Diabetes and in pancreas regeneration methodologies. The transcription factor (TF) sex determining region Y homeobox gene 9 (SOX9) has been identified as a key factor in human pancreas development but its role has not been well characterized. The expression of SOX9 during early pancreas development was analyzed by immunostaining of fixed embryonic and fetal sections in the context of other developmentally important TFs. Modulators of SOX9 function, downstream targets and upstream regulatory pathways were investigated in human cell lines using coimmunoprecipitation, small interfering RNA (siRNA) knockdown, quantitative polymerase chain reaction (qPCR), luciferase assays and small molecule signaling pathway inhibitors. SOX9 was expressed in epithelial progenitors from initial human pancreas specification, but became excluded from the periphery of the epithelium and developing islet cells as differentiation proceeded. It was co-expressed with important endocrine and exocrine differentiation factors during the early stages of development. Some factors, such as Nirenberg and Kim 2, homeobox family member, drosophila, homolog of, 2 (NKX2.2) showed differing expression profile compared to murine development, while the widespread expression of endocrine factors before expression of the pro-endocrine gene neurogenin 3 (NGN3) suggested that these factors play an important role in initiating endocrine specification. Two transcription factors, GATA-binding protein 4 (GATA4) and neurogenic differentiation 1 (NEUROD1), were found to interact with SOX9 in potentially developmentally relevant complexes. This prompted the search for downstream targets of these transcriptional complexes by in silico analysis, which identified an array of novel potential downstream targets. Luciferase assay analysis of a subset of these genes showed SOX9 to activate a regulatory region of NGN3, and inhibit the regulatory regions of carboxy peptidase A6 (CPA6), v-ets avian erythroblastosis virus E26 oncogene homolog1 (ETS1) and SPONDIN1. An additional target of SOX9, osteopontin (OPN), was identified from a microarray of Sox9 knockout mouse pancreata. Investigation of SOX9 and OPN regulation by the Hedgehog signalling pathway (HH) identified both factors to be regulated by the pathway, suggesting SOX9 may act as a mediator of HH signalling. This is the first study to identify a range of SOX9 targets relevant to human pancreas development. While further characterization is required this work has provided essential clues to the function of SOX9, and provides a detailed framework of SOX9 expression and targets for future pancreatic studies to build upon.
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Morais, da Silva Sara Luisa. "Sox9 : an SRY related gene involved in sex determination." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298429.
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Kim, Youngwoo. "Generation of transgenic mice for conditional overexpression of Sox9." Kyoto University, 2013. http://hdl.handle.net/2433/174810.
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Oshima, Masaya. "Rôles de SOX9 dans la cellule ß pancréatique humaine." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB040.
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Le pancréas est une glande amphicrine composée de cellules exocrines et de cellules endocrines. Parmi les cellules endocrines, organisées en îlot de Langerhans, les cellules ß sécrétrices d’insuline en réponse à des stimuli précis, sont essentielles pour l’homéostasie du glucose. Des perturbations tant au niveau qualitatif qu’au niveau quantitatif sont responsables de différentes pathologies telles les diabètes ou certaines formes de tumeurs endocrines. De récentes publications suggèrent que l’état de différenciation de la cellule ß pancréatique mature n’est pas immuable et montrent que le maintien d’un phénotype mature de la cellule est un processus dynamique. Différents modèles de souris mutantes (avec perte ou gain d’un facteur de transcription) montrent une perte de l’identité de la cellule ß. Cette plasticité altère la synthèse, le stockage et la sécrétion d’insuline. En plus de la perte d’identité, caractérisée par la diminution de l’expression de marqueurs de la cellule ß (MAFA, NKX6-1), les cellules ré-expriment des marqueurs de progéniteurs (NGN3, SOX9) : on parle de dédifférenciation. Cette dédifférenciation serait un mécanisme clé dans la diminution de la masse de cellules ß fonctionnelles au cours du diabète de type 2. Le but de ma thèse a été d’étudier le rôle du facteur de transcription SOX9 dans le contexte de la perte d’identité de la cellule ß humaine. SOX9 est exprimé dans les progéniteurs multipotents pancréatiques et joue plusieurs rôles cruciaux au cours du développement de l’organe. Bien qu’un rôle important de SOX9 fut attribué au cours de l’organogénèse du pancréas, il y a de plus en plus de données suggérant qu’il a des rôles additionnels dans le pancréas matures qui semble aussi importants que son rôle au cours du développement. C’est le cas notamment des cellules formant les canaux pancréatiques. D’un autre côté, pour les cellules endocrines, et plus particulièrement les cellules ß, SOX9, normalement absent de la cellule ß saine, est ré-exprimé dans ces cellules dans des conditions pathologiques (diabètes, tumeurs neuroendocrines du pancréas). Une expression ectopique de SOX9 dans les cellules ß induit un phénotype diabétique. Alors qu’il y a de plus en plus d’observation de l’expression de SOX9 dans la cellule ß, il y a très peu de connaissance sur les mécanismes moléculaires et les cibles de ce facteur de transcription dans les cellules ß humaines. Dans un premier temps, nous avons disséqué différents mécanismes impliqués dans l’induction de l’expression de SOX9. Pour cela, nous avons développé des conditions mimant des contextes pathologiques (diabètes, tumeurs neuroendocrines du pancréas VHL) en utilisant les cellules ß humaines EndoCßH1, récemment développées au sein du laboratoire. Dans un deuxième temps, nous avons développé des outils moléculaires afin d’identifier les cibles de SOX9 dans la cellule ß humaine (dominant positif, dominant négatif). Pour finir, nous avons analysé les cibles potentielles de SOX9 dans différentes conditions pathologiquesNo abstract
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Peacock, Jacqueline D. "The Role of Sox9 in Heart Valve Development and Disease." Scholarly Repository, 2011. http://scholarlyrepository.miami.edu/oa_dissertations/543.
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Heart valve structures open and close during the cardiac cycle to provide unidirectional blood flow through the heart, critical for efficient cardiovascular function. Valve dysfunction results in either incomplete opening or incomplete closure of the valve. Both types of valve dysfunction decrease efficiency of blood flow, increasing the load on the myocardium and leading to secondary heart disease such as pathological hypertrophy and heart failure. There are currently no effective treatments to prevent or slow the progression of valve disease, and there are no pharmacological treatments for advanced valve disease. Although most valve disease is associated with aging, increasing evidence suggests that valve disease often has origins in development. Congenital valvuloseptal defects affect many newborns, ranging from life-threatening malformations requiring immediate repair to more subtle, often undiagnosed defects that increase susceptibility to valve disease later in life. Therefore, an improved understanding of the mechanisms of heart valve formation and maintenance of adult valves may serve as an important step in improving valve disease treatment options. In this work, the mechanisms of normal valve development and the role of Sox9 in developing and mature valves are further studied. The temporal and spatial expression of extracellular matrix genes and proteins are examined throughout normal murine valve development. Sox9 function in the processes of valve development and valve maintenance is examined using mouse models of conditional Sox9 loss-of-function. Heart valve phenotypes in mice with reduced Sox9 function are examined throughout development and in adult mice with resultant calcific valve disease. The possible causative mechanisms of calcific valve disease in mice with reduced Sox9 function are further investigated by identification of novel possible targets of Sox9 transcriptional regulation. Together these studies improve our understanding of heart valve development, characterize a model of heart valve calcification with genetic etiology, and identify and characterize novel targets of Sox9.
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Hui, Man-ning, and 許文寧. "Investigating the role of SOX9 in human neural stem cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193481.
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Neural stem cells (NSCs) exist in both embryonic and adult neural tissues and are characterized by their self-renewal capacity and multipotency that contribute to the generation of three major cell types in the vertebrate central nervous system (CNS):neurons, oligodendrocytes and astrocytes. The tremendous therapeutic potential of NSCs to treat the neurodegenerative diseases and repair brain injuries has provoked intensive study in the molecular regulation of their induction, maintenance and differentiation.
Previous study reported that Sox9, a member of high-mobility-group(HMG) containing SoxE transcription factors family, plays important roles in regulating the formation and maintenance of NSCs in both mouse and chick CNS, as well as the cell fate switch between neuronal and glial. Whether it plays similar roles in human NSCs (hNSCs)is still unknown. My RT-qPCR analysis showed that SOX9is expressed at a basal level in human embryonic stem cells (hESCs) and up-regulated upon commitment into neural lineage and maintained at a high level in hESCs-derived hNSCs. I therefore hypothesized that SOX9 might also be involved in the induction, maintenance and differentiation of hNSCs.
To test this, two stable hESC lines(HES2)were generated with each constitutively expressing short hairpin RNA (shRNA) against SOX9andGL2 Luciferase (Luc, as control) respectively. Upon neural induction, SOX9-knock-down(KD) hESCs were able to commit neural lineage and differentiate into NSCs/neurospheres (NSPs), however, these NSCs exhibited reduced multipotency and glial marker (GALC, CD44) expressions but enhanced self-renewal compared to the shLuc NSCs. Hence, SOX9 is required for both the induction and maintenance of multipotent hNSCs. Strikingly, extensive TUJ1+ neurites and advance groupings of these neurites into bundles were observed in SOX9-KD NSPs after three days and seven days neuronal differentiation respectively, suggesting premature neurogenesis as a result of SOX9 ablation.
In addition, RT-qPCR analysis revealed down-regulated expression of NSC marker HES1but induced proneural basic helix-loop-helix transcription factor MASH1in shSOX9-1208 NSCs. The inhibitory role of HES1 on the expression and functions of MASH1 has been reported to be essential for the timely generation of neurons. Hence, ablation of SOX9 is likely to relieve the inhibition on MASH1activity via down-regulated HES1expression and leads to early neuronal differentiation. Expression of the potent neurite blocker NG2 was also found to be reduced in SOX9-KD NSCs which may explain the extensive neurite network observed. Altogether, similar to previous studies in mouse NSCs, SOX9 is also required for the induction and maintenance of hNSCs. However, this study further reveals a putative novel role of SOX9 in preventing premature neuronal differentiation by regulating the expressions of HES1 to counteract MASH1 function and NG2 to control neurite outgrowth.published_or_final_version
Biochemistry
Master
Master of Philosophy
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Rammah-Bouazza, Cyrine. "Implication de SOX9 et de MiniSOX9 dans la tumorigenèse colorectale." Thesis, Montpellier 1, 2012. http://www.theses.fr/2012MON1T020.
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SOX9 est un facteur de transcription, appartenant à la famille des protéines à domaine HMG, et connu pour réguler la transcription grâce à la liaison de ce domaine à l'ADN. Au laboratoire, il a été montré que SOX9 possédait des propriétés anti-oncogéniques, cependant, de façon paradoxale, SOX9 est surexprimé dans les tumeurs colorectales. Nous avons mis en évidence l'existence d'un nouveau variant d'épissage de SOX9, MiniSOX9, qui possède un effet dominant négatif vis-à-vis de l'activité transcriptionnelle de SOX9. MiniSOX9 est fortement exprimé dans les tumeurs en comparaison avec le tissu sain adjacent à la tumeur. Nous avons émis l'hypothèse que MiniSOX9 pourrait donc avoir, dans les tumeurs, un effet antagoniste à SOX9 et s'opposer à ses propriétés anti-oncogéniques. Grâce à la mise en place de modèles cellulaires tumoraux de surexpression de SOX9 et MiniSOX9, inductibles à la doxycycline, nous avons mis en évidence que SOX9 réduit la prolifération, la migration et l'invasion cellulaire. De manière surprenante, MiniSOX9 ne possède aucun effet sur la prolifération cellulaire, suggérant que les effets de SOX9 pourraient être dus à son activité transcriptionnelle. En revanche, SOX9 ainsi que MiniSOX9 réduisent la capacité clonale des cellules et leur capacité à former des tumorosphères. Dans ce cas, il serait probable que SOX9 et MiniSOX9 modulent l'activité de protéines partenairesSOX9 is an HMG transcription factor known to regulate transcription by binding of its HMG domain to DNA. We previously demonstrated that SOX9 has anti-oncogenic-properties but SOX9 is overexpressed in colon tumors when compared to adjacent healthy tissu. This overexpression appears paradoxical, unless its anti-oncogenic activity cannot be exert. In this study, we report the discovery of MiniSOX9, a new SOX9 splice variant, which is highly expressed in colon tumors. MiniSOX9 acts as a SOX9 dominant negative isoform. Our hypothesis was that MiniSOX9 antagonizes the SOX9 anti-oncogenic activity in tumors.Using tumors cells lines inducible for SOX9 and MiniSOX9 overexpression, we showed that SOX9 reduces cell proliferation, migration and invasion. Surprisingly, MiniSOX9 has no effect on cell proliferation, suggesting that SOX9 effects could be du to his transcriptionnal activity. However, SOX9 and MiniSOX9 decrease cell clonal ability and tumorosphere formation. In this case, it is likely that SOX9 and MiniSOX9 modulate the activity of proteins partners
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Hiramatsu, Yukiko. "Arid1a is essential for intestinal stem cells through Sox9 regulation." Kyoto University, 2019. http://hdl.handle.net/2433/243292.
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Genzer, Mary Ann. "Characterization of the Role of SOX9 in Cartilage-Specific Gene Regulation." Diss., CLICK HERE for online access, 2006. http://contentdm.lib.byu.edu/ETD/image/etd1164.pdf.
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Wunderle, Veronique Marie. "Effects of chromosome rearrangements observed in campomelic dysplasia patients on SOX9 expression." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624690.
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Jakob, S. "FOXL2 represses the testis-specific enhancer of Sox9 to maintain ovary differentiation." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/19694/.
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During normal testis development, SRY and SF1 up-regulate Sox9 expression via its testis-specific enhancer element (TESCO), which is crucial for the establishment of the male supporting cell lineage, the Sertoli cells. In contrast, during normal ovarian development, Sox9 expression needs to be down-regulated in the female supporting cells and failure results in XX female-to-male sex reversal. It was not known whether the repression of Sox9 expression is mediated via the TESCO regulatory element in XX gonads. FOXL2 is a forkhead transcription factor, expressed in the supporting cells of the ovary, but not testis, from 12.5~dpc onwards. Homozygous mutation of Foxl2 results in the up-regulation of Sox9 and other testis-specific genes in postnatal gonads, suggesting that FOXL2 plays an important role in proper ovarian development by maintaining the repression of Sox9. In this thesis, in vitro analyses demonstrate that FOXL2 can repress TESCO activity (as can other candidate ovarian determining genes, such as Dax1 and Sox4). The repressing effect of FOXL2 is more severe in the presence of ER. Several forkhead factor binding sites and EREs are present in the TESCO sequence, however mutation analyses showed that the repression effect is not mediated only through these. Moreover, FOXl2 can interact with SF1 and interfere with its ability to activate TESCO in vitro. In vivo studies showed that homozygous loss of Foxl2 results in the de-repression of TESCO activity in the remaining granulosa-like cells in the XX gonads, which correlates with the expression of endogenous Sox9. However, this de-repression occurs only after birth, getting more severe with age, suggesting that Foxl2 is the critical factor to repress TESCO activity in the adult ovary. Moreover, evidence is provided that the de-repression of Sox9 is independent from oocyte-depletion and solely due to the loss of Foxl2 as targeted deletion of oocytes did not result in an up-regulation of Sox9 expression. Further in vivo analyses indicate the involvement of Wnt signalling in the repression of TESCO activity during embryonic development, as TESCO becomes partially de-repressed in Wnt4 homozygous mutant mice before birth.
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Sono, Takashi. "THRAP3 interacts with and inhibits the transcriptional activity of SOX9 during chondrogenesis." Kyoto University, 2018. http://hdl.handle.net/2433/230996.
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Nguyen, Julie. "Rôle du facteur de transcription Sox9 dans l'homéostasie et la tumorigenèse intestinales." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT046.
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Le maintien de l’homéostasie intestinale met en jeu un dialogue entre l’épithélium, le microbiote et le système immunitaire. Les CSI assurent le renouvellement et la régénération de l’intestin en cas de lésions mais elles peuvent être également à l’origine des tumeurs intestinales. Le facteur de transcription Sox9 est un candidat intéressant comme régulateur clé de l’homéostasie intestinale car il est exprimé dans les CSI, les cellules de Paneth et les cellules tuft. De plus, Sox9 est indispensable à la différenciation des cellules de Paneth puisque l’inactivation de Sox9 chez l’embryon (modèle murin Sox9LoxP/LoxP ; Villin-Cre) conduit à une absence de cellules de Paneth. Au cours de ma thèse, nous avons dans un premier temps déterminé la fonction de Sox9 dans l’épithélium intestinal adulte à l’aide du modèle murin inductible : Sox9LoxP/LoxP ; Villin-CreERT2. Ainsi nous avons démontré que la délétion de Sox9 dans les cellules de Paneth conduit à des altérations structurales et fonctionnelles de ces dernières, qui induisent une altération de la biodiversité d’espèces bactériennes (dysbiose). La dysbiose est « sentie » par les cellules tuft qui initient une réponse immunitaire de type 2. Cette étude a révélé le rôle clé de Sox9 dans les cellules de Paneth adultes pour réguler l’homéostasie intestinale, en prévenant l’établissement d’un microbiote pro-inflammatoire. Les cellules tuft, via leur fonction de « sensing », sont capables en réponse à une dysbiose de moduler l’immunité mucosale et participent ainsi à la formation d’un cercle vicieux délétère. De plus, nous nous sommes intéressés à la biologie des CSI, en intégrant la contribution des propriétés des cellules de Paneth qui participent à l’établissement de la niche. Nous avons étudié les propriétés des cellules souches dans un contexte sain ou au cours de l’initiation tumorale. L’ensemble de nos données indiquent qu’en contexte sain, Sox9 est requis pour la régulation du destin cellulaire des CSI, c’est à dire l’équilibre entre l’auto-renouvellement des CSI et leur différenciation cellulaire. Les mécanismes régulés par Sox9 mettent en jeu le métabolisme cellulaire, un acteur clé du destin des cellules souches. Nos travaux montrent également que le maintien d’une niche intacte est nécessaire au contrôle du devenir des CSI. La délétion de Sox9 altère l’intégrité mitochondriale et favorise la production de ROS mitochondriaux qui pourrait moduler le destin des CSI vers un état différencié. En parallèle, nous avons mis en évidence que l’invalidation de Sox9 après l’acquisition d’un événement initiateur tel que la perte de fonction du gène suppresseur de tumeur Apc, affecte de façon majeure le destin des CSC vers un état souche ainsi que leur métabolisme cellulaire. L’évaluation du rôle du facteur de transcription Sox9 dans le contrôle de l’homéostasie métabolique permettra de mieux comprendre les mécanismes de régulation de la biologie des CSI, et de proposer à terme de nouvelles stratégies thérapeutiques ciblant les CSCThe intestinal homeostasis maintenance involves a permanent crosstalk between the epithelium, the microbiota and the immune system. ISC are responsible for the intestine renewal and regeneration, but they can also cause intestinal tumors. The Sox9 transcription factor is an interesting candidate as a key regulator of intestinal homeostasis because of its specific expression in ISC, Paneth cells and tuft cells. In addition, Sox9 is essential for the differentiation of Paneth cells since the loss of Sox9 in the mouse embryo (model Sox9LoxP / LoxP, Villin-Cre) leads to the absence of Paneth cells. First, we analysed the function of Sox9 in the adult intestinal epithelium using the inducible mouse model: Sox9LoxP / LoxP; Villin-CreERT2. We demonstrated that the deletion of Sox9 in adult Paneth cells leads to structural and functional alterations of Paneth cells, which induce alterations of bacterial diversity (dysbiosis). Dysbiosis is "sensed" by tuft cells that initiate a type 2 immune response. This study revealed the key role of Sox9 in adult Paneth cells to regulate intestinal homeostasis, thus preventing the establishment of a proinflammatory microbiota. Tuft cells, via their sensing function, are able to modulate mucosal immunity in response to a dysbiosis and thus participate in the formation of a vicious circle. In addition, we studied the biology of ISC, by integrating the contribution of Paneth cells properties that participate in the establishment of the niche. We analysed the properties of stem cells in a healthy context or during tumor initiation. Our data indicate that in a healthy context, Sox9 is required for the regulation of ISC fate, namely the balance between ISC self-renewal and differentiation. The mechanisms regulated by Sox9 involve cellular metabolism, a key player in the stem cells fate. Our work shows that an intact niche maintenance is necessary to control ISC fate. The deletion of Sox9 alters mitochondrial integrity and promotes mitochondrial ROS production that could modulate the ISC fate toward a differentiated state. In parallel, we demonstrated that Sox9 deletion concomitant with the acquisition of an initiating event such as the loss of function of the tumor suppressor gene Apc, affects the CSC and their cellular metabolism. The evaluation of the role of the Sox9 transcription factor in the control of metabolic homeostasis will provide a better understanding of the regulatory mechanisms in ISC biology, and eventually new therapeutic strategies targeting CSC might be proposed
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Soualhi, Salima. "Rôles de SOX9 dans l’auto-renouvellement et la différenciation de l’épithélium intestinal." Thesis, Montpellier 1, 2014. http://www.theses.fr/2014MON13519.
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Sox9 est un facteur de transcription exprimé au cours du développement de l'intestin et son expression est maintenue à l'âge adulte dans trois populations cellulaires : les cellules souches, les cellules de Paneth, et les cellules tuft. L'inactivation de Sox9 dans l'épithélium intestinal embryonnaire entraîne, chez l'adulte, une hyperplasie des cryptes ainsi que l'absence de cellules de Paneth. Ce projet de thèse vise à déterminer le rôle de Sox9 dans les cellules de Paneth (dont la fonction est altérée chez les patients atteints de la maladie de Crohn), à identifier les mécanismes par lesquels Sox9 régule la prolifération et à proposer des cibles de Sox9 dans les cellules tuft. À l'aide de modèles murins d'inactivation de Sox9 au niveau de l'épithélium intestinal adulte, nous avons montré que la perte de ce facteur conduit à une augmentation de la prolifération dans les cryptes, confirmant ainsi que Sox9 régule négativement ce processus. Nos résultats indiquent que Sox9 est essentiel au maintien de l'identité des cellules de Paneth et nous proposons qu'il assure cette fonction en réprimant des gènes requis pour la différenciation des cellules de Goblet : Muc2 et Klf4. La perte de Sox9 dans les cellules de Paneth s'accompagne d'une réduction importante des molécules antimicrobiennes, ce qui entraîne une dysbiose intestinale. Dans un environnement spécifique (en présence du « mouse norovirus »), les souris déficientes en Sox9 présentent une perméabilité intestinale augmentée et une susceptibilité à l'inflammation accrue. Les dysfonctionnements des réponses antimicrobiennes et immunitaires dans notre modèle sont comparables à ceux observés chez les patients atteints de la maladie de Crohn, suggérant une implication potentielle de Sox9 dans cette pathologie. De plus, ces altérations pourraient expliquer l'augmentation de l'apparition des tumeurs observée chez les souris dont l'épithélium intestinal est déficient en Sox9, dans le contexte d'une mutation du gène suppresseur de tumeur Apc. Enfin, nous avons identifié des gènes potentiellement régulés par Sox9 qui pourraient expliquer son rôle dans le contrôle de la prolifération. Ces découvertes seront importantes pour mieux comprendre le processus du renouvellement de l'épithélium intestinal et identifier précisément le rôle de Sox9 dans le maintien de l'homéostasie et au cours du processus de la tumorigenèse intestinaleSox9 is a transcription factor expressed during the intestinal development and its expression is maintained throughout adult age in at least three populations of cells: stem cells, Paneth cells and tuft cells. Sox9 inactivation in the embryonic intestinal epithelium leads to crypts hyperplasia and to the loss of the Paneth cell lineage. The aim of this project is to determine Sox9 function in the adult intestinal epithelium, especially its role in Paneth cells (which function is altered in patients affected by inflammatory diseases such as Crohn disease), to identify how Sox9 controls proliferation and to propose molecular targets of Sox9 in tuft cells. Using mice models to inactivate Sox9 in adult intestinal epithelium, we could show that Sox9 is required to limit proliferation in the crypts, thus validating the hypothesis that Sox9 regulates negatively proliferation. Our results indicate that Sox9 is essential to maintain Paneth cells identity and we proposed that it ensures this function by repressing genes specific for Goblet cells differentiation: Muc2 and Klf4. Loss of Sox9 in Paneth cells is associated with a reduction of antimicrobial molecules which causes intestinal dysbiosis. In a specific environment (in presence of the « mouse norovirus »), Sox9-deficient mice have a defective intestinal permeability and are more susceptible to inflammation. The dysfunctions of the mucosal defences and of immunity responses in our model resemble those observed in Crohn patients, thus suggesting a potential implication of Sox9 in this pathology. In addition, these alterations could be responsible for the increased susceptibility of our deficient model to develop tumors in the context of a mutation of the tumor suppressor gene Apc. We started to unravel potential molecular targets of Sox9 that are involved in the control of proliferation, that will be important to better understand Sox9 function in the intestinal epithelium self-renewal and to identify precisely Sox9 function to maintain homeostasis and during intestinal tumorigenesis
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Tsuda, Motoyuki. "The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis." Kyoto University, 2019. http://hdl.handle.net/2433/242378.
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Larsimont, Jean-Christophe. "Identification of the molecular mechanisms involved in the initiation, invasion and maintenance of basal cell carcinoma." Doctoral thesis, Universite Libre de Bruxelles, 2018. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/271467.
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Le carcinome basocellulaire (CBC) est le cancer le plus fréquent chez l’homme et est à lui seulresponsable de plus de cas que l’incidence cumulée de tous les autres cancers réunis. Des travauxrécents qui se sont intéressés aux étapes précoces de la tumorigenèse ont fourni un supportprécieux pour l’analyse du développement tumoral précoce. Ils ont mis en évidence le rôlecentral de gènes impliqués dans les progéniteurs embryonnaires des cellules souches du folliculepileux. Dans ce travail, nous avons étudié le rôle du facteur de transcription Sox9, un gène connupour être crucial dans la spécification de ces progéniteurs et dans les cellules souches du folliculepileux. Nous avons montré que Sox9 est requis pour la progression des lésions paranéoplasiquesvers les CBC et qu’il était également requis pour la maintenance des cellules cancéreuses. Enutilisant des méthodes d’analyse génomique de pointe, nous avons montré que Sox9 agit tantcomme un activateur que comme un répresseur de la transcription. Nous avons montré qu’ilpromeut directement le renouvellement cellulaire, l’invasion ainsi que la quiescence des cellulescancéreuses.Dans la seconde partie de ce travail, nous avons découvert le mécanisme d’action de l’inhibiteurd’Hedgehog Vismodegib sur les cellules cancéreuses. En utilisant des modèles génétiques desouris, nous avons montré que l’inhibiteur empêche la reprogrammation embryonnaire qui anormalement lieu durant la formation du CBC et qu’il promeut la différentiation des cellulescancéreuses vers une identité interfolliculaire, d’infundibulum ou sébacée suivant l’origine de cescellules. Nous avons également observé qu’une population caractérisée par l’expression du gèneLgr5 ainsi que par une activation de la voie de signalisation Wnt est plus résistante au Vismodegibchez la souris et nous avons trouvé des indices suggérant qu’il pourrait en être de même chezl’humain. Enfin, nous avons pu montrer que l’inhibition combinée des voies de signalisation Wntet Hedgehog annihile cette résistance et résulte en la disparition complète des CBCs.Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
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佘崢崢 and Tsang-tsang She. "Expression of SOX9 and type II collagen in the temporomandibular jointduring mandibular advancement." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B31973103.
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Kobayashi, Tomohito. "A-674563 increases chondrocyte marker expression in cultured chondrocytes by inhibiting Sox9 degradation." Kyoto University, 2018. http://hdl.handle.net/2433/232130.
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Zalzali, Hassan. "Etude du rôle du facteur de transcription SOX9 dans les cellules tumorales intestinales." Montpellier 2, 2008. http://www.theses.fr/2008MON20133.
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SOX9 appartient à la famille des facteurs de transcription à domaine HMG (High Mobility Group), responsable de sa liaison à l'ADN. Dans l'épithélium intestinal, SOX9 est exprimé dans les cellules indifférenciées du fond des cryptes. Par ailleurs, SOX9 est présent dans toutes les lignées de cellules tumorales intestinales (CTI) que nous avons étudiées. Ceci est probablement dû au fait que le gène de SOX9 est régulé par la voie de signalisation Wnt/β-caténine qui est constitutivement active dans 80% des tumeurs colorectales. Paradoxalement, nous avons montré au laboratoire que SOX9 diminue la prolifération cellulaire et augmente l'apoptose. Notre travail a consisté à étudier le rôle de SOX9 dans les CTI. Nous avons identifié la première cible transcriptionnelle directe de SOX9 dans l'épithélium intestinal. Il s'agit du suppresseur de tumeur CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) qui fait partie de la superfamille des immunoglobulines. En effet, SOX9 augmente son expression en interagissant avec une séquence de haute affinité située à 1. 4kb en aval de la séquence codante. Dans la mesure où SOX9 est présent dans les CTI, comment expliquer alors qu'il diminue la prolifération cellulaire, augmente l'apoptose et augmente l'expression d'un suppresseur de tumeur (CEACAM1)? Nous avons montré que l'activité endogène de SOX9 est faible dans les CTI. Nous avons par la suite mis en évidence MiniSOX9, un variant d'épissage de SOX9, qui inhibe l'activité de SOX9 par effet dominant négatif. Ceci suggère qu'il pourrait exister un antagonisme entre SOX9 et MiniSOX9 qui, peut être, serait impliqué dans la tumorigenèse coliqueIn the intestinal epithelium, the HMG-box transcription factor SOX9 is expressed in the undifferentiated cells from the bottom of the crypts. SOX9 is present in all colorectal cancer cells (CRCC) lines that we have studied. This is probably due to the fact that SOX9 gene is regulated by the Wnt / β-catenin signaling pathway that is constitutively active in 80% of colorectal tumors. Paradoxically, we have shown in the laboratory that SOX9 decreases cell proliferation and increased apoptosis. The aim of our work was to study the role of SOX9 in the CRCC. We have identified the tumor suppressor CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) as the first direct transcriptional target of SOX9 in the colon epithelium. CEACAM1 is a member of the immunoglobulin superfamily. Indeed, SOX9 increases CEACAM1 expression by interacting with a high affinity sequence, 1. 4kb downstream of the coding sequence. Since SOX9 is present in CRCC, how to explain that it decreases cell proliferation, increases apoptosis and increases the expression of a tumor suppressor (CEACAM1)? We have shown that endogenous SOX9 activity is weak in CRCC. We then highlighted MiniSOX9, a SOX9 splicing variant that inhibits SOX9 activity by a dominant negative effect. This suggests that an antagonism might exist between SOX9 and MiniSOX9 that could be implicated in colon tumorigenesis
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Athwal, Varinder. "Mechanism of SOX9 action as a route to diagnostic strategies in liver fibrosis." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/mechanism-of-sox9-action-as-a-route-to-diagnostic-strategies-in-liver-fibrosis(d047c8f8-332e-4aaa-8b4f-f5c2d1e91ab0).html.
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The work presented in this thesis aims to understand the role of the Sry-box transcription factor (SOX9) in liver fibrosis as a route to novel diagnostic strategies for the disease. Fibrosis of the liver is a major cause of morbidity and mortality in the UK characterised by progressive accumulation of extracellular matrix (ECM) proteins. End-stage disease is treated by transplantation, but this is limited by donor numbers. Although potentially reversible if diagnosed early, current methods of diagnosis are invasive and prone to sampling error. There is a critical need to improve current methods or develop novel strategies to determine fibrotic activity and disease progression. To address this, better mechanistic understanding of liver fibrosis is urgently required. My supervisor (Dr Piper Hanley) previously discovered ectopic expression of SOX9 as a novel mechanism to underlie aspects of liver fibrosis. This discovery allowed me to investigate the molecular genetic network in which SOX9 operates. Given SOX9’s seemingly central role, I identified novel target genes of SOX9 action, some of which have already been highlighted as candidate biomarkers, for new diagnostic strategies in liver fibrosis. Moreover, investigating the expression of SOX9 directly during liver fibrosis in human biopsy samples highlighted the factor as a prognostic marker of the disease. This thesis focussed on four key research areas: Identification of the inflammatory glycoprotein Osteopontin (OPN) as a direct target of SOX9. In addition to OPN, identification of four other downstream SOX9 targets as potential biomarkers of liver fibrosis severity. SOX9 expression in liver biopsies is described and quantified, highlighting its role as a new method to assess liver fibrosis progression. This work is being patented as a novel prognostic test in liver fibrosis. Finally, the role of SOX9 mediating ECM through inhibition of collagenases (e.g. MMP13) is described. Taken together, these data place SOX9 as a key mediator of liver fibrosis. However, translation of novel SOX9 targets as serum biomarkers of fibrosis and SOX9 as a marker of disease progression have ramifications on clinical practice, in particular assessing liver fibrosis progression.
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Östergren, Tiolina. "Identification of MYCN and SOX9 target genes and a study of drug treatment effects in medulloblastoma." Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-262085.
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Medulloblastoma (MB) is the most common malignant brain tumor affecting children. The transcription factors MYCN and SOX9 are associated with initiation, maintenance and recurrence of MB and are also connected to more aggressive tumors. In this study, a ChIP was performed to isolate DNA from genes that are transcriptionally regulated by these proteins. Identification of these target genes will reveal new potential drug targets and help us better understand the functions of MYCN and SOX9. The ChIP was not fully optimized during this project and the target genes were not sent for sequencing and identified. To study the connection between SOX9 and recurrence, cells with different levels of SOX9 were treated with drugs, after which cell viability was measured. No significant difference in resistance could be measured. Change in expression level of MYCN, SOX9 and other relevant genes after drug treatment was also studied. The results show an increase in SOX9 and HES1, suggesting that these genes are involved in tumor recurrence.
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Sugimoto, Yuki. "Scx[+]/Sox9[+] progenitors contribute to the establishment of the junction between cartilage and tendon/ligament." Kyoto University, 2014. http://hdl.handle.net/2433/185191.
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Hosokawa, Shinichi. "Impact of Sox9 Dosage and Hes1-mediated Notch Signaling in Controlling the Plasticity of Adult Pancreatic Duct Cells in Mice." Kyoto University, 2015. http://hdl.handle.net/2433/200490.
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Grigorova, Fialka. "Characterization of the Role Nuclear Bmp2 (nBmp2) Plays in Regulating Gene Expression." BYU ScholarsArchive, 2011. https://scholarsarchive.byu.edu/etd/3196.
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The nBmp2 protein was first identified in a DNA affinity chromatography/mass spectrometry screen designed to detect proteins that interact with a cartilage-specific enhancer element (called D/E) from the type XI collagen gene Col11a2. The transcription factor SOX9, a protein from the Sox (SRY-related HMG box) family, binds to and activates gene expression from this enhancer. nBmp2 has no transcriptional activity of its own on this enhancer, but when co-transfected with SOX9 it increases SOX9's activation of D/E nearly 2-fold. SOX9 also activates cartilage-specific enhancer elements from the Col2a1, Col27a1, and Col9a1 genes. The purpose of this project was to determine 1) whether nBmp2 similarly effects SOX9-dependent expression from these enhancers, and 2) whether it does so by binding (either directly or indirectly) to the Col2a1, Col27a1, and Col9a1 enhancers. The work described in this thesis has shown that nBmp2 increases luciferase levels produced from three enhancer/reporter plasmids, but it does so without binding directly to the enhancers. This work has opened up a new area of exploration into the function of the novel protein nBmp2 to examine its potential effects on a variety of different gene regulatory processes.
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Yuan, Xiaodong [Verfasser], and Steven [Akademischer Betreuer] Dooley. "SOX9 in the development and chemotherapy of cholangiocarcinoma (CCA) / Xiaodong Yuan ; Betreuer: Steven Dooley." Heidelberg : Universitätsbibliothek Heidelberg, 2018. http://d-nb.info/1177691647/34.
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Mak, Chi-yan Angel, and 麥志昕. "Bioinformatic and functional approaches to identify potential SOX9 target genes in inner ear development." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hdl.handle.net/10722/193405.
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Passeron, Thierry. "De la mélanogénèse au mélanome : le rôle clef de SOX9 dans la cellule mélanocytaire." Nice, 2008. http://www.theses.fr/2008NICE4012.
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Nous avons montré que SOX9 était exprimé in vitro et in vivo par les mélanocytes et jouait un rôle clé dans la mélanogenèse induite par les radiations ultraviolettes de type B (UVB). Activé par l’AMP cyclique puis de la protéine kinase A (PKA), SOX9 va augmenter l’expression des enzymes de la mélanogenèse en agissant directement sur le facteur de transcription MITF, augmentant in fine la production de mélanine au sein des mélanosomes. Par ailleurs, nous avons également montré qu’Agouti Signaling Protein (ASP), connue pour inhiber la mélanogenèse, était capable de diminuer l’expression de SOX9 dans les mélanocytes. Cette action permet d’expliquer, du moins en partie, le mécanisme d’action encore méconnu d’ASP. Dans un second temps nous avons étudié l’expression et le rôle de SOX9 dans les cellules de mélanome. Nous avons montré que l’expression de SOX9 était faible ou nulle dans la grande majorité des biopsies de mélanomes que nous avons analysées. SOX9 inhibe la prolifération des cellules de mélanomes en activant directement et indirectement le promoteur de p21. Par ailleurs, nous avons montré que SOX9 pouvait restaurer la sensibilité des cellules de mélanome à l’acide rétinoïque en diminuant l’expression de PRAME. La surexpression de SOX9 réduit sensiblement la tumorigenicité des cellules de mélanomes in vivo chez la souris et ex vivo sur des modèles de peaux reconstruites humaines. Nous avons enfin montré que des agents capables d’augmenter ou d’activer SOX9, tels que la prostaglandine D2 (PGD2), reproduisaient son action sur la prolifération des mélanomes et permettaient également de restaurer la sensibilité à l’acide rétinoïqueWe showed that SOX9 is expressed in vitro and in vivo by melanocytes and plays a key role in ultraviolet B (UVB) induced melanogenesis. After the activation by cyclic AMP and protein kinase A (PKA), SOX9 increases the expression of melanogenic enzymes by acting directly on the transcription factor MITF, leading to an increased production of melanin within melanosomes. We also showed that Agouti Signalling Protein (ASP), known to inhibit melanogenesis, was able to decrease the expression of SOX9 in melanocytes. This action could explain, at least partially, the poorly understood mechanism of action of ASP. Then, we studied the expression and the role of SOX9 inhibits the proliferation of melanoma cells by acting and indirectly on p21 promoter. In the same time, SOX9 restores the sensitivity of melanoma cells to retinoic acid by decreasing the expression of PRAME. The over expression of SOX9 strongly reduces the tumorigenicity of melanoma cells in vivo in mice and ex vivo in reconstructed skin models. Finally, chemical agents, capable of increasing or activating SOX9, such as prostaglandin D2 (PGD2), reproduce its action on proliferation of melanomas and also restore the sensitivity to retinoic acid
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Sumi, Eriko. "SOX9 regulates the expression of Col4a2 through transactivating its enhancer element in mesangial cells." Kyoto University, 2007. http://hdl.handle.net/2433/135766.
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She, Tsang-tsang. "Expression of SOX9 and type II collagen in the temporomandibular joint during mandibular advancement." Hong Kong : University of Hong Kong, 2002. http://sunzi.lib.hku.hk/hkuto/record.jsp?B25314117.
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Au, Y. K. Tiffany. "Investigating the molecular mechanisms of campomelic dysplasia in a mouse with a Sox9 gene mutation." Thesis, Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/HKUTO/record/B39557236.
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Bastide, Pauline. "Les rôles du facteur de transcription SOX9 dans le contrôle de l'homéostasie de l'épithélium intestinal." Montpellier 1, 2007. http://www.theses.fr/2007MON13513.
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Dans l’épithélium intestinal, Sox9 est spécifiquement exprimé par les cellules souches/progénitrices et les cellules de Paneth. L'expression de Sox9 est contrôlée par la voie Wnt/b-caténine qui joue un rôle central dans le contrôle de l’homéostasie intestinale. Cependant, les processus moléculaires qui assurent la spécificité des réponses cellulaires à ces signaux restent à identifier. Afin d’analyser la fonction de Sox9 in vivo, nous avons généré des souris dont l’épithélium intestinal est déficient en Sox9. En l‘absence de Sox9 des défauts de la différenciation sont observés tout le long de l’épithélium intestinal. De plus, une hyperplasie généralisée des cryptes et des cryptes d’apparence dysplasique, dans lesquelles, des gènes cibles de la voie de signalisation Wnt sont surexprimés, ont également été observées dans l’épithélium intestinal des souris déficientes en Sox9. Les résultats obtenus au cours de ma thèse ont permis de déterminer le rôle central de Sox9, non seulement en tant que cible transcriptionnelle de la voie Wnt canonique, mais aussi en tant que régulateur de cette voie de signalisation pour le contrôle de l’homéostasie de l’épithélium intestinalThe HMG-box transcription factor Sox9 is expressed in the intestinal epithelium, specifi cally, in stem/ progenitor cells and in Paneth cells. Sox9 expression requires an active β-catenin–Tcf complex, the transcriptional effector of the Wnt pathway. This pathway is critical for numerous aspects of the intestinal epithelium physiopathology, but processes that specify the cell response to such multipotential signals still remain to be identifi ed. We inactivated the Sox9 gene in the intestinal epithelium to analyze its physiological function. Sox9 inactivation affected differentiation throughout the intestinal epithelium, with a disappearance of Paneth cells and a decrease of the goblet cell lineage. Additionally, the morphology of the colon epithelium was severely altered. We detected general hyperplasia and local crypt dysplasia in the intestine, and Wnt pathway target genes were up-regulated. These results highlight the central position of Sox9 as both a transcriptional target and a regulator of the Wnt pathway in the regulation of intestinal epithelium homeostasis
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Flammiger, Anna. "Expression von Nestin und Osteopontin in Melanomzelllinien und die Rolle der Transkriptionsfaktoren BRN2, SOX9 und SOX10." Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-109457.
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Mak, Chi-yan Angel, and 麥志昕. "Bioinformatic studies of gene regulation involving SOX9 and HOXB3 withreference to craniofacial development and other processes." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B37465405.
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Patzina, Tobias [Verfasser], Eva [Gutachter] Klopocki, and Johannes [Gutachter] Wirbelauer. "Genetische Veränderungen am SOX9 Lokus bei Pierre-Robin-Sequenz / Tobias Patzina ; Gutachter: Eva Klopocki, Johannes Wirbelauer." Würzburg : Universität Würzburg, 2019. http://d-nb.info/1194313876/34.
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Dupasquier, Sébastien. "SOX9, un lien moléculaire entre voie Wnt/APC et PKCalpha dans l'épithélium intestinal sain et tumoral." Montpellier 1, 2008. http://www.theses.fr/2008MON1T041.
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Les cellules tumorales présentent des variations parfois importantes du taux de certaines protéines qui leur procurent un avantage sélectif de croissance par rapport aux cellules normales dont elles dérivent. Ces variations peuvent résulter d'altérations de l'ADN, premier support de l'information génétique, la transcription, la maturation et/ou la stabilité de l'ARN messager, ou encore la traduction et/ou la dégradation de la protéine. Les protéines kinases C (PKC) sont impliquées dans de nombreux processus cellulaires associés à la tumorigenèse, notamment le contrôle de la prolifération, de la différenciation et de l'apoptose. Or, d'importantes variations de leurs niveaux d'accumulation sont observées dans de nombreuses tumeurs humaines. Néanmoins, le lien causal entre les mécanismes régulant la transcription, la traduction ou encore la stabilité et la dégradation des PKC et ces variations est rarement établi. Nous avons pour notre part démontré que l'expression de PKCα est réprimée aussi bien in vitro qu'in vivo par le facteur de transcription SOX9 dans les cellules épithéliales intestinales. Cette répression ne nécessite pas l'interaction de SOX9 avec l'ADN via son domaine HMG mais est médiée par un nouveau mécanisme impliquant la région centrale de SOX9, très conservée entre les membres du groupe des SOXE (SOX8, 9, 10). Puisque SOX9 est une cible de la voie Wnt/APC dans les cellules épithéliales intestinales, nos résultats établissent un lien moléculaire entre voie Wnt/APC et PKCα et permettent d'expliquer pourquoi PKCα est diminuée dans les cancers colorectaux qui présentent pour 80% d'entre eux une activation constitutive de la voie Wnt/APC.
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Furuyama, Kenichiro. "Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine." Kyoto University, 2011. http://hdl.handle.net/2433/142558.
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Hyon, Capucine. "Etude des gènes impliqués dans le déterminisme gonadique chez l'homme." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066493/document.
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Les anomalies du développement sexuel recouvrent un spectre phénotypique large. Les hommes XX présentent dans la majorité des cas un développement testiculaire normal, lié à la présence SRY sur un des chromosomes X. Dans 10% des cas, aucune cause n’est retrouvée. Chez les femmes, l’origine de l’insuffisance ovarienne prématurée (IOP) n’est identifiée que dans 20% des cas. L’objectif de cette thèse a été d’identifier de nouveaux mécanismes moléculaires impliqués dans le développement gonadique, testiculaire et ovarien, ainsi que dans son fonctionnement. L’étude d’une cohorte de patients DSD 46,XX SRY négatifs a mis en évidence une duplication de la région RevSex dans un désert génique en amont de SOX9 chez quatre patients. Ceci a permis de redéfinir la région minimale impliquée dans l'activation de l'expression de SOX9 à une taille maximale de 41.9 kb et de proposer un mécanisme permettant cette expression chez des hommes XX. Le séquençage d’exome chez dix patients de la cohorte n’a pas mis en évidence de mutations dans des gènes d’intérêts. L’ensemble de ces résultats pose la question du rôle des régions régulatrices dans la survenue des DSD.L’analyse d’une cohorte de patientes ayant une IOP a permis d'identifier des délétions incluant le gène CPEB1. Des études précédentes chez la souris ont montré son implication dans le développement folliculaire. Le séquençage du gène CPEB1 dans la cohorte n'a pas mis en évidence de mutation pathogène. Ce travail a permis de montrer que la délétion impliquant le gène CPEB1est une cause rare mais récurrente d'IOP et concerne environ 1% des patientes. Une microdélétion contenant le gène CASP3 un gène de la voie des caspases impliquée dans la régulation du pool folliculaire a également été identifiée chez une patiente. L'ensemble de ces résultats montre l'intérêt de l'étude génétique des patients présentant une anomalie du développement de la gonade ou de son fonctionnement par des techniques d'étude globale du génomeDisorders of Sex Development (DSD) can be identified in new-born and during infancy but also in adults because of infertility. Most 46,XX testicular DSD have a normal testicular development due to the presence of the SRY gene at the tip of one of their X chromosome. However, the genetic causes of 46,XX-SRY negative testicular DSD remain poorly defined. In women, disorders of gonadal development can be responsible for primary ovarian insufficiency (POI) and genetic causes are identify in only 20% of cases. The aim of this thesis was to identify molecular mechanisms involved in gonadal development and in its functioning. The cohort study of 46,XX testicular DSD identified four patients with a duplication in the previously reported RevSex region located about 550 kb upstream of SOX9. One duplication allowed us to refine the minimal region associated with 46,XX-SRY negative DSD to a 40.7–41.9 kb element. Exome sequencing of 10 patients from the cohort did not show any mutation in genes implicated in DSD or in new candidate genes. These results raise questions about the role of the regulatory sequences in the onset of DSD.The cohort study of POI patients identified three patients carrying a microdeletion including CPEB1 a good candidate gene for POI as study in mice showed the implication of CPEB1 in follicular development. Sequencing CPEB1 gene did not identified any mutation. Therefore, heterozygous deletion of CPEB1 gene leading to haploinsufficiency could be responsible for POI in humans. This microdeletion is rare but recurrent and was identified in about 1% of patients with POI. Another microdeletion containing CASP3 gene that belongs to the caspase family, which is implicated in the regulation of the follicular pool, was identified in a patient. Further studies are needed to confirm the role of CASP3 in POI. These results demonstrate the importance of genetic study of patients presenting with DSD or POI using whole genome techniques
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Mak, Chi-yan Angel. "Bioinformatic studies of gene regulation involving SOX9 and HOXB3 with reference to craniofacial development and other processes." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B37465405.
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Stöckl, Sabine [Verfasser], and Achim [Akademischer Betreuer] Göpferich. "Der Einfluss von Sox9 auf Zellvitalität und Differenzierungspotential von adulten mesenchymalen Stammzellen / Sabine Stöckl. Betreuer: Achim Göpferich." Regensburg : Universitätsbibliothek Regensburg, 2013. http://d-nb.info/1043631488/34.
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Benko, Sabina. "Altérations génomiques à grande distance d'éléments non-codants conservés et dérégulation d'expression tissu-spécifique au locus SOX9." Paris 5, 2010. http://www.theses.fr/2010PA05T039.
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SOX9, gène majeur du développement, est localisé au sein d'un désert génique représentant son domaine de régulation. Les mutations du gène SOX9 résultent en un syndrome polymalformatif la dysplasie campomelique (PC). Les endophénotypes de la PC dans leurs formes isolés - séquence de Pierre Robin (SPRi) et anomalies de différentiation sexuelle (DSDi) — peuvent survenir suite à des altérations (translocations, délétions, mutations ponctuelles) des régions non-codantes au locus SOX9. Des études in vitro et in vivo indiquent que ces altérations, localisées a grande distance par rapport à SOX9 (>l,2Mb/SPR; >500kb/DSD), concernent les éléments conservés au cours de l'évolution ayant une fonction régulatrice d'expression tissu et stade spécifique. Les altérations identifiées chez les patients SPRi ou ADSi affecteraient l'expression tissu spécifique respectivement dans le mésenchyme mandibulaire ou les gonades pendant que les autres domaines d'expression de SOX9 resteraient intactsSQX9 is a major developmental gene mapping to a vast gene desert that encompasses its regulatory domain. The SOX9 gene coding equence mutations result in campomelic dysplaisa (CD), a complex polymalformative syndrome. We showed that alterations of non-coding sequences (translocations, deletions or point mutations) at the SOX9 locus result in isolated CD endophenotypes namely Pierre Robin sequence (iPRS) and disorders of sex developpement (iDSD). Both in vitro and in vivo studies indicate that those alterations, located at great distance with respect to SOX9 coding sequences (>1,2Mb/iPRS; >500kb/iDSD), comprise regions conserved throughout the evolution that function as regulatory elements driving tissue specific gene expression of SOX9. We suggest that alterations identified in iPRS and iDSD patients represent a tissue specific loss of SOX9 expression in the mandibular mesenchyme or the developing gonad respectively, while other territories of normal SOX9 expression remain intact
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Davis, Matthew Grauden. "RHOX8 ABLATION USING A NOVEL SIRNA TRANSGENIC MOUSE MODEL YIELDS DOWN REGULATION OF SEX-DETERMINATION GENE, SOX9." OpenSIUC, 2012. https://opensiuc.lib.siu.edu/theses/1036.
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The Reproductive Homeobox X-linked, Rhox, genes encode transcription factors that are expressed exclusively in the testis, epididymis, placenta, and ovary and are therefore good candidates to regulate postnatal reproductive events. The founding member of this 33 gene cluster Rhox5, previously known as Pem, is important in male mice for both spermatogenesis and sperm maturation. This is supported by the findings that Rhox5-null mice are hypofertile due to increased apoptosis of meiotic germ cells in the testis as well as motility defects in epididymal sperm. Rhox5 was also the first homeobox gene to exhibit stage specific androgen sensitivity exclusive to Sertoli cells during spermatogenesis. Within the Rhox family, only RHOX8 shows expression in Sertoli cells at time intervals similar to that of RHOX5. Interestingly, while Rhox8 exhibits high expression in Sertoli cells it does not appear to be dependent upon androgens for transcription. The co-localization of these genes supports the hypothesis that RHOX5 and RHOX8 may exhibit partially redundant functions in the testis, and potentially explain why Rhox5-null animals are subfertile and not infertile. However, due to the androgen dissimilarity between Rhox5 and Rhox8 aforementioned it is possible that RHOX8 also exhibits functionally unique expression in the male gonad as well. Therefore, we sought to ablate Rhox8, and potentially derive Rhox5/Rhox8 double knockouts to better assess these questions. However, due to the proximity of Rhox5 and Rhox8 on the X chromosome, recombination of individual knockout lines produced by traditional strategies would be unlikely to succeed. To circumvent this issue, we used a novel tissue-specific RNAi approach to knockdown RHOX8 in vivo. Our knockdown system used the Rhox5 proximal promoter which contains regulatory elements for expression of the Rhox8-siRNA transgene in Sertoli cells. Candidate siRNAs were evaluated for knockdown of RHOX8 in Sertoli cell lines, and the most efficient was used to produce 11 independent founder lines. Among these founders the majority of the males failed to produce any subsequent litters. However, backcrossed littermates from female founder lines have exhibited knockdown of RHOX8 in total testis lysates using Western blot analysis. Immunohistochemical analysis confirmed Sertoli cell specific RHOX8 protein knockdown as well as knockdown of Sertoli cell marker, SOX9. However, other control targets, GATA1, AR, and RHOX5; maintain normal expression patterns. Rhox8-knockdown and Sox9-regulation was also observed at the mRNA level via real-time qPCR, showing significant knockdown of both transcripts when compared to wild-type animals. Further characterization revealed that this single knockdown of RHOX8 sufficiently yields a subfertile phenotype. Therefore, the central hypothesis of this study is that RHOX8 is imperative for normal sperm output, an essential gene regulator in the adult testis, and possibly employs an important role during embryonic testis development.