The division of neural progenitor cells provides the cellular substrate from which the nervous system is sculpted during development. The d-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 d-protocadherins increases cell divisions of neural progenitors in the hindbrain. This increase is due to mis-regulation of Wnt/b-catenin signaling, as this pathway is upregulated in d-protocadherin mutants and inhibition of this pathway blocks the increase in cell division. Furthermore, the d-protocadherins can be present in complex with the Wnt receptor Ryk, and Ryk is required for the increased proliferation in protocadherin mutants. Thus, d-protocadherins are novel regulators of Wnt/ b-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.
The proliferation of neural progenitor cells provides the cellular substrate from which the nervous system is sculpted during development. The δ-protocadherin family of homophilic cell adhesion molecules is essential for the normal development of the nervous system and has been linked to an array of neurodevelopmental disorders. However, the biological functions of δ-protocadherins are not well-defined. Here, we show that the δ-protocadherins regulate proliferation in neural progenitor cells, as lesions in each of six, individual δ-protocadherin genes increase cell division in the developing hindbrain. Moreover, Wnt/β-catenin signaling is upregulated in δ-protocadherin mutants and inhibition of the canonical Wnt pathway occludes the observed proliferation increases. We show that the δ-protocadherins physically associate with the Wnt receptor Ryk, and that Ryk is required for the increased proliferation in protocadherin mutants. Thus, the δ-protocadherins act as novel regulators of Wnt/β-catenin signaling during neural development and could provide lineage-restricted local regulation of canonical Wnt signaling and cell proliferation.
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