Enteric nervous system (ENS) development involves reciprocal interactions between enteric neural crest-derived cells (ENCCs) and their environment as they migrate along the intestine, differentiate, and become patterned. Here, Allan Goldstein, Nandor Nagy and colleagues examine these interactions and reveal that sonic hedgehog (Shh) patterns the extracellular matrix to control enteric nervous system development in chick embryos (p. ). They report that Shh is expressed specifically in the epithelium of the gut, which harbours an ENS, but not in the epithelium of the bursa of Fabricius, a structure that is associated with the gut but does not have an ENS. They then show, using chick-quail tissue recombinations in which hindgut epithelium is replaced with epithelium from the bursa of Fabricius, that ENS development is perturbed in the absence of hindgut epithelium. Hypothesising that epithelium-derived Shh controls hindgut ENS formation, the authors demonstrate that Shh inhibition causes hyperganglionosis, whereas Shh overexpression causes aganglionosis owing to decreased proliferation and premature differentiation of ENCCs. Finally, they reveal that modulating Shh activity dramatically alters the expression of ECM proteins, such as versican and collagen IX, that are known regulators of neural crest cell migration. These, together with other findings, suggest that epithelial-derived Shh acts indirectly on the developing ENS by regulating the intestinal microenvironment.
