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

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

Author information

1
Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136, USA.
2
Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065, USA.
3
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Chemistry, Scripps Florida, Jupiter, FL 33458, USA.
5
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
6
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
7
Departments of Surgery and Biochemistry and Molecular Biology, Molecular Oncology Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
8
Cell Division and Cancer Group, Spanish National Cancer Research Centre, 28029 Madrid, Spain.
9
Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136, USA. Electronic address: nayad@miami.edu.

Abstract

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.

PMID:
25843713
PMCID:
PMC4401652
DOI:
10.1016/j.celrep.2015.03.016
[Indexed for MEDLINE]
Free PMC Article

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