Casein kinase 1δ is an APC/C<sup>Cdh1</sup> 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 Ayad

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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 anaphasepromoting complex/cyclosome (APC/CC<sup>dh1</sup>) ubiquitin ligase, and conditional deletion of the APC/ CC<sup>dh1</sup> activator Cdh1 in cerebellar GCPs results in higher levels of CK1δ. APC/CC<sup>dh1</sup> also downregulates CK1δ during cell-cycle exit. Therefore, we conclude that APC/CC<sup>dh1</sup> 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.

Original languageEnglish (US)
Pages (from-to)249-260
Number of pages12
JournalCell Reports
Volume11
Issue number2
DOIs
StatePublished - 2015

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Penas, C., Govek, E. E., Fang, Y., Ramachandran, V., Daniel, M., Wang, W., Maloof, M. E., Rahaim, R. J., Bibian, M., Kawauchi, D., Finkelstein, D., Han, J. L., Long, J., Li, B., Robbins, D. J., Malumbres, M., Roussel, M. F., Roush, W. R., Hatten, M. E., & Ayad, N. (2015). Casein kinase 1δ is an APC/C<sup>Cdh1</sup> substrate that regulates cerebellar granule cell neurogenesis. Cell Reports, 11(2), 249-260. https://doi.org/10.1016/j.celrep.2015.03.016