Wnt signaling

Process of Differentiation

Sci. Signal.  18 Nov 2008:
Vol. 1, Issue 46, pp. ec393
DOI: 10.1126/scisignal.146ec393

The atypical transmembrane receptor tyrosine kinase (RTK) Ryk is a Wnt receptor that plays important roles in axon guidance and neurite outgrowth. Ryk is an unusual RTK because its intracellular domain (ICD) does not exhibit tyrosine kinase activity, so the mechanism by which it mediates Wnt signaling is unclear (see commentary by Zhong). Noting that Ryk is found in neural progenitor cells (NPCs) and neurons, Lyu et al. investigated its role in NPC function. Immunohistochemical analysis of brain sections showed that Ryk knockout (KO) mice had fewer mature cortical plate neurons than did their wild-type (WT) counterparts, without having any differences in the number or proliferative ability of their NPCs. Whereas Ryk was detected on the surface of NPCs from WT mice, Ryk was less abundant at the surface of mature neurons. Instead, the Ryk ICD was detected in the nucleus in neurons. Lentiviral-mediated expression of WT Ryk in Ryk-deficient NPCs restored their ability to differentiate into neurons in culture, but expression of a mutant Ryk lacking its transmembrane domain did not. In cultured NPCs, addition of an inhibitor of γ-secretase, which cleaves ICDs from other transmembrane proteins, prevented the nuclear accumulation of Ryk ICD. Lentiviral expression of Wnt3 in NPCs stimulated their differentiation into neurons and induced more nuclear localization of Ryk ICD compared to that of control NPCs. Wnt3-induced neuronal differentiation was blocked in NPCs expressing a dominant-negative Ryk that lacked an ICD. Together, these data suggest that Wnt-stimulated neuronal differentiation depends on γ-secretase–dependent processing of Ryk and nuclear localization of its ICD, leading the authors to speculate that the Ryk ICD may regulate the expression of Wnt-target genes through a mechanism independent of β-catenin.

J. Lyu, V. Yamamoto, W. Lu, Cleavage of the Wnt receptor Ryk regulates neuronal differentiation during cortical neurogenesis. Dev. Cell 15, 773–780 (2008). [PubMed]

W. Zhong, Going nuclear is again a winning (Wnt) strategy. Dev. Cell 15, 635–636 (2008). [PubMed]