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Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model
E M Southard-Smith1, L Kos, W J Pavan
1Mouse Embryology Section, Laboratory of Genetic Disease Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-4472, USA.
Nature Genetics
|January 13, 1998
Summary
Sox10 deficiency causes neural crest defects leading to Hirschsprung disease (HSCR) and embryonic lethality in mice. This finding identifies SOX10 as a potential candidate gene for human HSCR cases with unknown genetic origins.
Area of Science:
- Developmental biology
- Genetics
- Neuroscience
Background:
- Hirschsprung disease (HSCR) is a neurocristopathy defined by absent enteric ganglia in the distal colon.
- Some HSCR patients exhibit neural crest-derived melanocyte deficiencies, known as Hirschsprung-Waardenburg syndrome.
- Murine models have identified key genes involved in HSCR, including Ednrb, Edn3, cRet, and GDNF.
Purpose of the Study:
- To investigate the genetic basis of the spontaneous mouse model of HSCR, known as Dom.
- To determine the role of the transcription factor Sox10 in neural crest development and its relation to HSCR.
- To explore SOX10 as a candidate gene for human HSCR cases lacking identified genetic causes.
Main Methods:
- Characterization of the Dom mouse model, including heterozygous and homozygous phenotypes.
- Analysis of Sox10 gene expression and function in wild-type and Dom mutant embryos.
- Assessment of neural crest cell survival and differentiation in Dom mutants.
Main Results:
- The Dom mutation results from premature termination of the Sox10 gene.
- Sox10 expression is disrupted in Dom mutant embryos, alongside the HSCR gene Ednrb.
- Defective Sox10 function leads to loss of neural crest derivatives through apoptosis, causing HSCR phenotypes and embryonic lethality in homozygous Dom mice.
- Sox10 is crucial for peripheral nervous system development.
Conclusions:
- Sox10 is essential for the development of neural crest-derived enteric ganglia and peripheral nervous system.
- The Dom mouse model provides critical insights into the function of Sox10 in neurocristopathies.
- SOX10 is proposed as a candidate gene for individuals with idiopathic HSCR.