Genetic interaction between Sox10 and Zfhx1b during enteric nervous system development

INSERM U955, IMRB, Equipe 11, Creteil, F-94010, France.
Developmental Biology (Impact Factor: 3.55). 03/2010; 341(2):416-28. DOI: 10.1016/j.ydbio.2010.02.036
Source: PubMed


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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    • "Authors clearly showed that L1cam; Sox10 double mutants defects observed resulted from excessive cell death of neural crest cells prior to entering the gut. In contrast, and similar to Sox10; Zeb2 DH (Stanchina et al., 2010), severe ENS defects in Sox10; Itgb1 embryos were observed from E11.5 onwards, suggesting that cooperativity between SOX10 and β1-integrins is critical as ENCC migrate along the gut. However, we cannot exclude the possibility that crosstalk between SOX10 and β1-integrins occurs earlier, but that the conditional ablation strategy used here prevented its observation. "
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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: A link between factors governing brain development and the development of the ENS is not surprising as both processes are largely controlled by the same or similar neural growth factors which are expressed at more or less in the same spatio-temporal time frame. Hirschsprung's disease (HSCR) occurs as an isolated phenotype in 70% of cases but is associated with other congenital abnormalities and syndromic phenotypes in the remainder, with CNS anomalies making up 6.78%. These associations may be underestimated and are possibly pathogenetically linked to genetic associations and probable gene-gene interaction. In this review we explore known syndromes and other ENS associations of HSCR, looking at possible pathogenetic associations. We point out that borderline cognitive abilities, attention-deficit disorders and possible epileptic seizures in Hirschsprung's patients should be fully investigated. We recognise that this group of patients remain a challenge from a clinical and functional management point of view, and suggest possible management guidelines.
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    ABSTRACT: First described by Danish pediatrician Harald Hirschsprung, Hirschsprung disease (HSCR) is a disorder of the enteric nervous system characterized by the absence of variable length of the submucous (Meissner's) and myenteric (Auerbach's) plexuses in the distal gut. As a defect in neural crest-derived cell population, Hirschsprung disease is considered a neurocristopathy. While HSCR was originally observed in sporadic cases, the advent of lifesaving surgical intervention has also given rise to the observation of familial forms of HSCR. Subsequently, its presentation in familial, sporadic, and syndromic form illuminated the genetics of HSCR. As this work has progressed the ret proto-oncogene (RET), a receptor tyrosine kinase has emerged as a central player in the development of HSCR, most frequently modified in effect by the contributions of risk alleles at other loci. This has been exemplified by the recent characterization of risk variants in a noncoding RET regulatory element, establishing it as a model for the study of multigenic disorders. © 2012 Springer Science+Business Media, LLC. All rights reserved.
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