Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Neurocristopathies, including Hirschsprung disease (HSCR) and neuroblastoma (NB), arise from developmental errors in neural crest cells.
• Congenital central hypoventilation syndrome (CCHS) is strongly associated with specific PHOX2B gene mutations, yet the underlying molecular mechanisms remain unclear.

Purpose of the Study:

• To elucidate the molecular pathogenesis of CCHS-associated neurocristopathies by investigating the functional consequences of non-polyalanine repeat expansion mutations in the PHOX2B gene.
• To establish a mouse model that recapitulates CCHS, HSCR, and NB phenotypes.

Main Methods:

• Generation of a mouse model with a non-polyalanine repeat expansion mutation in the Phox2b gene.
• Analysis of enteric and sympathetic ganglion progenitor development in mutant embryos.
• Assessment of gene expression, cell proliferation, and differentiation.
• Investigation of PHOX2B's transcriptional activity on target genes and regulatory elements.

Main Results:

• The mouse model exhibited clinical features of CCHS, HSCR, and NB.
• Mutant embryos showed impaired progenitor proliferation and glial lineage bias, linked to sustained SOX10 expression.
• PHOX2B mutations exerted dominant-negative effects on DBH transactivation and altered transcriptional regulation of a SOX10 enhancer, acting as a gain-of-function mutation.

Conclusions:

• Non-polyalanine repeat expansion mutations in PHOX2B are both dominant-negative and gain-of-function, disrupting autonomic nervous system development.
• PHOX2B's regulation of SOX10 is critical for autonomic ganglion development and implicated in CCHS pathogenesis.