1. Hirschsprung Disease and Activation of Hedgehog Signaling via GLI1-3 Mutations 
Heather M. Young, Lincon A. Stamp 
Gastroenterology 
Volume 149, Issue 7, Pages (December 2015)
DOI: /j.gastro
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2. Figure 1
Gli proteins and Sufu (Suppressor of fused), which are members of the Hedgehog (Hh) signaling pathway, form a regulatory network with Sox10 that is required for the development of the enteric nervous system. Gli proteins are transcription factors that are effectors of Hh signaling and they act as activators and/or repressors. Binding of Hh ligands to Patched receptors (Ptch) results in the activation of a variety of genes by Gli activators (GliA; Gli repressors are not shown). Sufu is a negative regulator of GliA. Note that the multiple events between binding of Hh ligands to Ptch receptors and activation of Gli proteins are indicated by a single dotted line. (A) In wild-type enteric neural crest-derived cells (NCC), which give rise to enteric neurons and glia, GliA regulates Sox10 expression in addition to a variety of other Hh target genes. Sox10 in turn directly or indirectly regulates progenitor maintenance (not shown), migration and the development of glia. Sox10 also negatively regulates Sufu expression. Genetic inactivation of Sufu in NCC in mice (B) enhances GliA activity (thicker black lines). Thus, Sufu mutant mice can be used as a model of HSCR patients with gain-of-function mutations in GLI. Loss of Sufu leads to an up-regulation of Sox10 and other Hh target genes, and the mutants exhibit defects in directional enteric NCC migration and increased glia:neuron ratios. Mice lacking Sufu in NCCs die around E13.5, which is before enteric NCCs have colonized the entire gut, so it is not known whether they have distal aganglionosis and hence a Hirschsprung disease-like phenotype. Previous studies have shown that mutant mice with reduced Sox10 also show defects in enteric NCC migration and glial cell development, so it seems that correct levels of Sox10 are essential for the development of the enteric nervous system.
Gastroenterology  , DOI: ( /j.gastro )
Copyright © 2015 AGA Institute Terms and Conditions