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Smek1/2 is a nuclear chaperone and cofactor for cleaved Wnt receptor Ryk, regulating cortical neurogenesis

Significance Receptor-like tyrosine kinase (Ryk) is a Wnt receptor and is important for many developmental processes, including cranial facial development, neurogenesis, and axon guidance. However, little is known about the role of the intracellular domain, Ryk-ICD, in signal transduction. Its downstream targets are also unknown. We have previously shown that Ryk-ICD is located in the cytoplasm of neural stem cells whereas it moves into the nucleus upon neuronal differentiation. In this study, we discovered that Smek1/2 function as a chaperone for Ryk-ICD during its nuclear localization and that both Smek and Ryk-ICD associate with chromatin to regulate the transcription of downstream target genes and neural differentiation. The receptor-like tyrosine kinase (Ryk), a Wnt receptor, is important for cell fate determination during corticogenesis. During neuronal differentiation, the Ryk intracellular domain (ICD) is cleaved. Cleavage of Ryk and nuclear translocation of Ryk-ICD are required for neuronal differentiation. However, the mechanism of translocation and how it regulates neuronal differentiation remain unclear. Here, we identified Smek1 and Smek2 as Ryk-ICD partners that regulate its nuclear localization and function together with Ryk-ICD in the nucleus through chromatin recruitment and gene transcription regulation. Smek1/2 double knockout mice displayed pronounced defects in the production of cortical neurons, especially interneurons, while the neural stem cell population increased. In addition, both Smek and Ryk-ICD bound to the Dlx1/2 intergenic regulator element and were involved in its transcriptional regulation. These findings demonstrate a mechanism of the Ryk signaling pathway in which Smek1/2 and Ryk-ICD work together to mediate neural cell fate during corticogenesis.