Genetic interaction between Sox10 and Zfhx1b during enteric nervous system development.

INSERM U955, IMRB, Equipe 11, Creteil, F-94010, France.
Developmental Biology (Impact Factor: 3.87). 03/2010; 341(2):416-28. DOI: 10.1016/j.ydbio.2010.02.036
Source: PubMed

ABSTRACT The involvement of SOX10 and ZFHX1B in Waardenburg-Hirschsprung disease (hypopigmentation, deafness, and absence of enteric ganglia) and Mowat-Wilson syndrome (mental retardation, facial dysmorphy and variable congenital malformations including Hirschsprung disease) respectively, highlighted the importance of both transcription factors during enteric nervous system (ENS) development. The expression and function of SOX10 are now well established, but those of ZFHX1B remain elusive. Here we describe the expression profile of Zfhx1b and its genetic interactions with Sox10 during mouse ENS development. Through phenotype analysis of Sox10;Zfhx1b double mutants, we show that a coordinated and balanced interaction between these two genes is required for normal ENS development. Double mutants present with more severe ENS defects due to decreased proliferation of enteric progenitors and increased neuronal differentiation from E11.5 onwards. Thus, joint activity between these two transcription factors is crucial for proper ENS development and our results contribute to the understanding of the molecular basis of ENS defects observed both in mutant mouse models and in patients carrying SOX10 and ZFHX1B mutations.

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    ABSTRACT: SOX10 involvement in syndromic form of Hirschsprung disease (intestinal aganglionosis, HSCR) in humans as well as developmental defects in animal models highlights the importance of this transcription factor in control of the pool of enteric progenitors and their differentiation. Here, we characterized the role of SOX10 in cell migration and its interactions with β1-integrins. To this end, we crossed the Sox10(lacZ/+) mice with the conditional Ht-PA::Cre; beta1(neo/+) and beta1(fl/fl) mice and compared the phenotype of embryos of different genotypes during enteric nervous system (ENS) development. The Sox10(lacZ/+);Ht-PA::Cre; beta1(neo/fl) double mutant embryos presented with increased intestinal aganglionosis length and more severe neuronal network disorganization compared to single mutants. These defects, detected by E11.5, are not compensated after birth, showing that a coordinated and balanced interaction between these two genes is required for normal ENS development. Use of video-microscopy revealed that defects observed result from reduced migration speed and altered directionality of enteric neural crest cells. Expression of β1-integrins upon SOX10 overexpression or in Sox10(lacZ/+) mice was also analyzed. The modulation of SOX10 expression altered β1-integrins, suggesting that SOX10 levels are critical for proper expression and function of this adhesion molecule. Together with previous studies, our results strongly indicate that SOX10 mediates ENCC adhesion and migration, and contribute to the understanding of the molecular and cellular basis of ENS defects observed both in mutant mouse models and in patients carrying SOX10 mutations.
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    ABSTRACT: Hirschsprung disease (HSCR) is a human congenital disorder, defined by the absence of ganglia from variable lengths of the colon. These ganglia comprise the enteric nervous system (ENS) and are derived from migratory neural crest cells. The inheritance of HSCR is complex, often non-Mendelian and characterized by variable penetrance. Although extensive research has identified many key players in the pathogenesis of Hirschsprung disease, a large number of cases remain genetically undefined. Therefore, additional unidentified genes or modifiers must contribute to the etiology and pathogenesis of Hirschsprung disease. We have discovered that Tcof1 may be one such modifier. Haploinsufficiency of Tcof1 in mice results in a reduction of vagal neural crest cells (NCC) and their delayed migration along the length of the gut during early development. This alone however is not sufficient to cause colonic aganglionosis as alterations in the balance of NCC proliferation and differentiation ensures NCC colonize the entire length of the gut of Tcof1(+/-) mice by E18.5. In contrast, Tcof1 haploinsufficiency is able to sensitize Pax3(+/-) mice to colonic aganglionosis. Although, Pax3 heterozygous mice do not show ENS defects, compound Pax3;Tcof1 heterozygous mice exhibit cumulative apoptosis which severely reduces the NCC population that migrates into the foregut. In addition, the proliferative capacity of these NCC is also diminished. Taken together with the opposing effects of Pax3 and Tcof1 on NCC differentiation, the synergistic haploinsufficiency of Tcof1 and Pax3 results in colonic aganglionosis in mice and may contribute to the pathogenesis of Hirschsprung disease.
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    ABSTRACT: The SOX10 transcription factor is a characteristic marker for migratory multipotent neural crest (NC) progenitors as well as several of their differentiated derivatives. The involvement of SOX10 in Waardenburg-Hirschsprung disease (pigmentation defects, deafness and intestinal aganglionosis) and studies of mutant animal models have contributed significantly to the understanding of its function in neural crest cells (NCC) in general and in the melanocytes and enteric nervous system (ENS) in particular. Cell-based studies have further demonstrated the important roles of this transcription factor in maintaining the NC progenitor cell number and in determining glial cell fate. Phenotypic variability observed among patients presenting with SOX10 mutations is in agreement with molecular genetics and animal model studies, which revealed that SOX10 cooperates with different partner factors; a number of genetic modifiers of SOX10 have been identified. This study reviews the expression, regulation, and function of SOX10 in normal development of the ENS and in disease conditions, as well as the genetic and molecular interactions of SOX10 with other ENS genes/factors. We also discuss future research areas. Further understanding of SOX10 function will benefit from genomic and cell biological studies that integrate the cell-intrinsic molecular mechanisms and the interactions of the enteric NCC with the niche environment.
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