Editors' ChoiceDevelopmental Biology

Building the enteric nervous system

Sci. Signal.  26 Jan 2016:
Vol. 9, Issue 412, pp. ec17
DOI: 10.1126/scisignal.aaf3056

The enteric nervous system is the nervous system of the gut. Development of the ganglia involves the migration, proliferation, and differentiation of enteric neural crest–derived cells (ENCCs). These processes involve two additional parts of the developing gut, the epithelial cells that form the most interior layer of the gut and the subepithelial mesenchyme that surrounds the epithelial layer. Nagy et al. found that, prior to ganglion development, the epithelia produce the morphogen Sonic hedgehog (Shh) and the mesenchymal cells are positive for the Shh receptor Patched, but that the ENCCs are not positive for Shh receptors. Chick embryo implantation of isolated epithelium from a nongut tissue (the bursa of Fabricius), which does not produce Shh, that was cultured with hindgut mesenchyme resulted in the development of large ganglia in these ectopic tissues, and the ganglia were abnormally close to the epithelial layer. Exposure of explants of chick embryo intestine to a pharmacological inhibitor of Shh activity resulted in abnormally large ganglia that were distributed throughout the mesenchyme, whereas application of exogenous Shh resulted in the complete absence of ganglia. Shh increased the proliferation of the mesenchymal cells, whereas blocking Shh activity promoted the proliferation of the ENCCs. The data indicated that Shh acted on the mesenchyme to indirectly affect ENCCs. Indeed, manipulating Shh signaling in embryonic gut explants altered the distribution of extracellular matrix proteins, including chondroitin sulfate proteoglycans (CSPGs), which inhibit ENCC migration. Exogenous Shh resulted in an increase in CSPGs such that they became evenly distributed throughout the mesenchymal layer; blocking Shh activity reduced the abundance of the matrix proteins to a narrow subepithelial region. Virally induced overexpression of Shh in the developing chick embryo gut increased the abundance of CSPGs in the gut and resulted in the absence of ENCCs in the hindgut mesenchyme and blocked the development of ganglia. Application of the growth factor GDNF to explanted chick embryo gut induced the migration of ENCCs out of the gut toward the source of GDNF, and Shh blocked this response. Application of Shh after the ENCCs had migrated out of the gut tissue into the substrate matrix did not reduce their migration, consistent with the inhibitory effect of Shh requiring the mesenchymal cells of the gut tissue. Thus, Shh mediates a complex developmental process involving cells from all three of the embryonic layers.

N. Nagy, C. Barad, H. K. Graham, R. Hotta, L. S. Cheng, N. Fejszak, A. M. Goldstein, Sonic hedgehog controls enteric nervous system development by patterning the extracellular matrix. Development 143, 264–275 (2016). [PubMed]