δ-Protocadherins regulate neural progenitor cell division by antagonizing Ryk and Wnt/β-catenin signaling

The division of neural progenitor cells provides the cellular substrate from which the nervous system is sculpted during development. The delta-protocadherin family of homophilic cell adhesion molecules is essential for the development of the vertebrate nervous system and is implicated in an array of neurodevelopmental disorders. We show that lesions in any of six, individual delta-protocadherins increases cell divisions of neural progenitors in the hindbrain. This increase is due to mis-regulation of Wnt/beta-catenin signaling, as this pathway is upregulated in delta-protocadherin mutants and inhibition of this pathway blocks the increase in cell division. Furthermore, the delta-protocadherins can be present in complex with the Wnt receptor Ryk, and Ryk is required for the increased proliferation in protocadherin mutants. Thus, delta-protocadherins are novel regulators of Wnt/beta-catenin signaling that may control the development of neural circuits by defining a molecular code for the identity of neural progenitor cells and differentially regulating their proliferation.