δ-protocadherins control neural progenitor cell proliferation by antagonizing Ryk and Wnt/β-catenin signaling

Abstract

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.

A complete Protocadherin-19 ectodomain model for evaluating epilepsy-causing mutations and potential protein interaction sites

“…The interaction with GABA A R is facilitated by the intracellular domains of hs PCDH19 and hs GABA A R (Bassani et al, 2018). Conversely, the interaction with Ryk has been narrowed to either the extracellular domains or transmembrane domains of dr Pcdh19 and dr Ryk (Biswas et al, 2020). Thus, Ryk is another protein that could potentially interact with the key regions in EC5 and EC6 of Pcdh19.…”