Editors' ChoiceDevelopmental Biology

Taking Shh signaling up a Notch

Sci. Signal.  02 Jun 2015:
Vol. 8, Issue 379, pp. ec144
DOI: 10.1126/scisignal.aac6635

Spatial and temporal gradients of several morphogens, including Notch and Sonic hedgehog (Shh), specify neural and glial cell fates from neural progenitor cells (NPCs). In the ventral spinal cord, NPCs closest to the Shh-secreting ventral floorplate cells become the p3 lineage, which produces interneurons and astroglia, whereas cells farther from the floorplate and exposed to lower concentrations of Shh form the pMN lineage, which produces motor neurons and oligodendrocytes. Kong et al. found that Notch signaling promotes trafficking of Shh signaling mediators into primary cilia, thereby enhancing the responsiveness of NPCs to Shh. In vivo, increasing the amount of Notch signaling in cells normally destined to become the p3 and pMN lineages ("Notch-On" spinal cords) increased the number of p3 cells and reduced the number of pMN cells; inactivating Notch signaling in these same regions ("Notch-Off" spinal cords) increased the number of pMN cells at the expense of p3 cells. These changes in the proportion of p3 and pMN cells induced corresponding changes in the numbers of differentiated motor neurons, oligodendrocytes, and astrocytes at later embryonic stages. Shh binds to the transmembrane receptor Patched (PTCH), thereby relieving PTCH-mediated repression of the transmembrane protein Smoothened (Smo) to enable intracellular signaling. In several types of human and mouse cell lines and primary cells, including NPC-like human neuroepithelial cells generated from embryonic stem cells, Notch signaling promoted the accumulation of Smo and PTCH1 in primary cilia, a major site of Shh signaling, and increased the expression of Shh-responsive genes. In embryos, Smo exhibited greater ciliary localization in the cells destined to become the p3 lineage compared with those cells destined to form the pMN lineage. In Notch-Off spinal cords, the amount of Smo present in cilia in the cells in these two regions was reduced, and the size of region in which Smo was localized to cilia was also reduced. In Notch-On spinal cords, the region in which Smo was localized to cilia extended further dorsally than it did in controls. Notch-dependent trafficking of PTCH1 was a prerequisite for the entry of Smo into primary cilia (see Yabut et al.). Thus, Notch signaling ensures that ventral NPCs can respond to Shh by promoting the proper subcellular localization of Shh signaling components.

J. H. Kong, L. Yang, E. Dessaud, K. Chuang, D. M. Moore, R. Rohatgi, J. Briscoe, B. G. Novitch, Notch activity modulates the responsiveness of neural progenitors to Sonic hedgehog signaling. Dev. Cell 33, 373–387 (2015). [PubMed]

O. Yabut, S. J. Pleasure, K. Yoon, A Notch above Sonic hedgehog. Dev. Cell 33, 371–372 (2015). [PubMed]