Casein kinase 1? is an APC/C(Cdh1) substrate that regulates cerebellar granule cell neurogenesis.

ABSTRACT: Although casein kinase 1? (CK1?) 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? or treatment of GCPs with a highly selective small molecule inhibits GCP expansion. In contrast, CK1? overexpression increases GCP proliferation. Thus, CK1? appears to regulate GCP neurogenesis. CK1? 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?. APC/C(Cdh1) also downregulates CK1? during cell-cycle exit. Therefore, we conclude that APC/C(Cdh1) controls CK1? levels to balance proliferation and cell-cycle exit in the developing CNS. Similar studies in medulloblastoma cells showed that CK1? holds promise as a therapeutic target.

SUBMITTER: Penas C 

PROVIDER: S-EPMC4401652 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature