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

Cell Rep. 2015 Apr 14;11(2):249-60. doi: 10.1016/j.celrep.2015.03.016. Epub 2015 Apr 2.


Although casein kinase 1δ (CK1δ) 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 CK1δ or treatment of GCPs with a highly selective small molecule inhibits GCP expansion. In contrast, CK1δ overexpression increases GCP proliferation. Thus, CK1δ appears to regulate GCP neurogenesis. CK1δ 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 CK1δ. APC/C(Cdh1) also downregulates CK1δ during cell-cycle exit. Therefore, we conclude that APC/C(Cdh1) controls CK1δ levels to balance proliferation and cell-cycle exit in the developing CNS. Similar studies in medulloblastoma cells showed that CK1δ holds promise as a therapeutic target.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome / biosynthesis*
  • Anaphase-Promoting Complex-Cyclosome / genetics
  • Animals
  • Casein Kinase Idelta / biosynthesis*
  • Casein Kinase Idelta / genetics
  • Cdh1 Proteins / biosynthesis*
  • Cdh1 Proteins / genetics
  • Cell Cycle / genetics
  • Cell Proliferation / genetics
  • Central Nervous System / growth & development*
  • Central Nervous System / metabolism
  • Cerebellum / growth & development
  • Cerebellum / metabolism
  • Gene Expression Regulation, Developmental
  • HeLa Cells
  • Humans
  • Mice
  • Neurogenesis / genetics*
  • Neurons / metabolism
  • RNA Interference
  • Signal Transduction


  • Cdh1 Proteins
  • Fzr1 protein, mouse
  • Anaphase-Promoting Complex-Cyclosome
  • Casein Kinase Idelta