Double Duty for Sonic Hedgehog

Science's STKE  08 Apr 2003:
Vol. 2003, Issue 177, pp. tw138-TW138
DOI: 10.1126/stke.2003.177.tw138

During development, neurons extend axons that migrate in response to chemoattractant and chemorepulsive cues. Netrin-1 is one chemoattractant secreted by the floor plate and periventricular zone of the neural tube that attracts commissural axons of the spinal cord to the midline. However, netrin-1-deficient mice show limited proper migration of commissural axons, which suggests that another chemoattractant may be secreted by the floor plate. Charron et al. show that sonic hedgehog (Shh), a known morphogen (a secreted signal that forms gradients controlling cellular differentiation), is also a chemoattractant secreted by the floor plate for commissural axons. Embryos of mice lacking a floor plate (by loss of a gene essential for its formation) show a more severe loss of proper commissural axon projection than that seen in embryos lacking just netrin-1 alone. Netrin-1 and Shh stimulated axon turning in isolated explants of embryonic rat spinal cord. However, only netrin-1 stimulated axon outgrowth. Shh-stimulated axon turning was inhibited by application of cyclopamine, an inhibitor of the Shh receptor smoothened (Smo). Analysis of markers for neuronal differentiation indicated that Shh was not causing re-patterning of the embryonic spinal cord at embryonic day 11, the time in which Shh was tested for chemoattractant activity. Finally, conditional knockout of the Smo (in a wild-type netrin-1 background) in commissural neurons showed that loss of Shh signaling resulted in highly defasciculated projection patterns and incomplete projection to the midline. Thus, Shh appears to be both a morphogen and a chemoattractant.

F. Charron, E. Stein, J. Jeong, A. P. McMahon, M. Tessier-Lavigne, The morphogen Sonic hedgehog is an axonal chemoattractant that collaborates with Netrin-1 in midline axon guidance. Cell 113, 11-23 (2003). [Online Journal]