Casein Kinase 1δ Is an APC/CCdh1 Substrate that Regulates Cerebellar Granule Cell Neurogenesis

Although casein kinase 1 delta (CK1 delta) is at the center of multiple signaling pathways, its role in the expansion of CNS progenitor cells is unknown. Using mouse cerebellar granule cell progenitors (GCPs) as a model for brain neurogenesis, we demonstrate that the loss of CK1 delta or treatment of GCPs with a highly selective small molecule inhibits GCP expansion. In contrast, CK1 delta overexpression increases GCP proliferation. Thus, CK1 delta appears to regulate GCP neurogenesis. CK1 delta is targeted for proteolysis via the anaphase-promoting complex/cyclosome (APC/C-Cdh1) ubiquitin ligase, and conditional deletion of the APC/C-Cdh1 activator Cdh1 in cerebellar GCPs results in higher levels of CK1 delta. APC/C-Cdh1 also downregulates CK1 delta during cell-cycle exit. Therefore, we conclude that APC/C-Cdh1 controls CK1 delta levels to balance proliferation and cell-cycle exit in the developing CNS. Similar studies in medulloblastoma cells showed that CK1 delta holds promise as a therapeutic target.