Genetic interaction between Sox10 and Zfhx1b during enteric nervous system development

INSERM U955, IMRB, Equipe 11, Creteil, F-94010, France.
Developmental Biology (Impact Factor: 3.64). 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.

  • [Show abstract] [Hide abstract]
    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.
    Pediatric Surgery International 12/2010; 27(4):347-52. DOI:10.1007/s00383-010-2807-y
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Signaling by the many ligands of the TGFβ family strongly converges towards only five receptor-activated, intracellular Smad proteins, which fall into two classes i.e. Smad2/3 and Smad1/5/8, respectively. These Smads bind to a surprisingly high number of Smad-interacting proteins (SIPs), many of which are transcription factors (TFs) that co-operate in Smad-controlled target gene transcription in a cell type and context specific manner. A combination of functional analyses in vivo as well as in cell cultures and biochemical studies has revealed the enormous versatility of the Smad proteins. Smads and their SIPs regulate diverse molecular and cellular processes and are also directly relevant to development and disease. In this survey, we selected appropriate examples on the BMP-Smads, with emphasis on Smad1 and Smad5, and on a number of SIPs, i.e. the CPSF subunit Smicl, Ttrap (Tdp2) and Sip1 (Zeb2, Zfhx1b) from our own research carried out in three different vertebrate models.
    Cytokine & growth factor reviews 11/2011; 22(5-6):287-300. DOI:10.1016/j.cytogfr.2011.11.006
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hirschsprung's disease is a congenital disorder that occurs in 1:5000 live births. It is characterised by an absence of enteric neurons along a variable region of the gastrointestinal tract. Hirschsprung's disease is classified as a multigenic disorder, because the same phenotype is associated with mutations in multiple distinct genes. Furthermore, the genetics of Hirschsprung's disease are highly complex and not strictly Mendelian. The phenotypic variability and incomplete penetrance observed in Hirschsprung's disease also suggests the involvement of modifier genes. Here, we summarise the current knowledge of the genetics underlying Hirschsprung's disease based on human and animal studies, focusing on the principal causative genes, their interactions, and the role of modifier genes.
    World Journal of Gastroenterology 12/2011; 17(45):4937-44. DOI:10.3748/wjg.v17.i45.4937


Available from