SUFU-GLI-SOX10 in enteric nervous system development and Hirschsprung disease

Abstract

Hirschsprung (HSCR) disease is defined by deficit of enteric neurons, which are derived from neural crest cells (NCC). Aberrant glial differentiation of NCCs represents a possible cause of HSCR, but the gene machinery involved remains unclear. Here we identify several mutations in GLI1-3 in HSCR patients that all lead to increased GLI transcriptional activity on Sox10 expression. We show Sufu-Gli expression is dynamically regulated during NCC differentiation and correlates with the segregation into neurons and glia. Importantly, Sufu-Gli and Sox10 form a regulatory loop to control neuronal versus glial lineage differentiation and migration of NCCs. Aberrantly high Gli activity caused by loss of Sufu disturbs the reciprocal balance of Sufu-Gli and Sox10, resulting in disrupted enteric NCC chain migration, defective axonal fasciculation and intestinal hypoganglionosis. Collectively, GLI mutations were identified for the first time in HSCR patients, and perturbed Sufu-Gli-Sox10 regulatory nexus contributes to HSCR pathogenesis in mouse and human.