title: Casein kinase 1δ is an APC/C(Cdh1) substrate that regulates cerebellar granule cell neurogenesis.
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.
authors.affiliation: Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136, USA.
authors.forename: Clara
authors.initials: C
authors.lastname: Penas
authors.affiliation: Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Eve-Ellen
authors.initials: EE
authors.lastname: Govek
authors.affiliation: Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136, USA.
authors.forename: Vimal
authors.initials: V
authors.lastname: Ramachandran
authors.affiliation: Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Daniel
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Wang
authors.affiliation: Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136, USA.
authors.forename: Marie E
authors.initials: ME
authors.lastname: Maloof
authors.affiliation: Department of Chemistry, Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Rahaim
authors.affiliation: Department of Chemistry, Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bibian
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kawauchi
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.affiliation: Department of Chemistry, Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Jeng-Liang
authors.initials: JL
authors.lastname: Han
authors.affiliation: Departments of Surgery and Biochemistry and Molecular Biology, Molecular Oncology Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Long
authors.affiliation: Departments of Surgery and Biochemistry and Molecular Biology, Molecular Oncology Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Departments of Surgery and Biochemistry and Molecular Biology, Molecular Oncology Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Robbins
authors.affiliation: Cell Division and Cancer Group, Spanish National Cancer Research Centre, 28029 Madrid, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Martine F
authors.initials: MF
authors.lastname: Roussel
authors.affiliation: Department of Chemistry, Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
authors.affiliation: Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Hatten
authors.affiliation: Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136, USA. Electronic address: nayad@miami.edu.
authors.forename: Nagi G
authors.initials: NG
authors.lastname: Ayad
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D048148:Casein Kinase Idelta / Q000096:biosynthesis* / Q000235:genetics; D064200:Cdh1 Proteins / Q000096:biosynthesis* / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002490:Central Nervous System / Q000254:growth & development* / Q000378:metabolism; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction
chemical_list: D064200:Cdh1 Proteins; C577585:Fzr1 protein, mouse; D064173:Anaphase-Promoting Complex-Cyclosome; D048148:Casein Kinase Idelta
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