Casein Kinase 1δ Is an APC/CCdh1 Substrate that Regulates Cerebellar Granule Cell Neurogenesis
Clara Penas,
Eve-Ellen Govek,
Yin Fang,
Vimal Ramachandran,
Mark Daniel,
Weiping Wang,
Marie E. Maloof,
Ronald J. Rahaim,
Mathieu Bibian,
Daisuke Kawauchi,
David Finkelstein,
Jeng-Liang Han,
Jun Long,
Bin Li,
David J. Robbins,
Marcos Malumbres,
Martine F. Roussel,
William R. Roush,
Mary E. Hatten,
Nagi G. Ayad
Affiliations
Clara Penas
Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136, USA
Eve-Ellen Govek
Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065, USA
Yin Fang
Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065, USA
Vimal Ramachandran
Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136, USA
Mark Daniel
Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136, USA
Weiping Wang
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
Marie E. Maloof
Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136, USA
Ronald J. Rahaim
Department of Chemistry, Scripps Florida, Jupiter, FL 33458, USA
Mathieu Bibian
Department of Chemistry, Scripps Florida, Jupiter, FL 33458, USA
Daisuke Kawauchi
Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
David Finkelstein
Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Jeng-Liang Han
Department of Chemistry, Scripps Florida, Jupiter, FL 33458, USA
Jun Long
Departments of Surgery and Biochemistry and Molecular Biology, Molecular Oncology Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Bin Li
Departments of Surgery and Biochemistry and Molecular Biology, Molecular Oncology Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA
David J. Robbins
Departments of Surgery and Biochemistry and Molecular Biology, Molecular Oncology Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Marcos Malumbres
Cell Division and Cancer Group, Spanish National Cancer Research Centre, 28029 Madrid, Spain
Martine F. Roussel
Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
William R. Roush
Department of Chemistry, Scripps Florida, Jupiter, FL 33458, USA
Mary E. Hatten
Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065, USA
Nagi G. Ayad
Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136, USA
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/CCdh1) ubiquitin ligase, and conditional deletion of the APC/CCdh1 activator Cdh1 in cerebellar GCPs results in higher levels of CK1δ. APC/CCdh1 also downregulates CK1δ during cell-cycle exit. Therefore, we conclude that APC/CCdh1 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.
