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PLoS One. 2014 Sep 24;9(9):e107943. doi: 10.1371/journal.pone.0107943. eCollection 2014.

Talpid3-binding centrosomal protein Cep120 is required for centriole duplication and proliferation of cerebellar granule neuron progenitors.

Author information

1
Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York, United States of America.
2
Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York, United States of America; Department of Human Anatomy, Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
3
Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York, United States of America; Institute of Developmental Immunology, College of Life Science, Shandong University, Jinan, Shandong, China.
4
Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York, United States of America.
5
Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York, United States of America; Institute of Life Science, Nanjing University, Nanjing, Jiangsu, China.
6
Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
7
Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York, United States of America; Department of Cell Biology and Development, Weill Medical College of Cornell University, New York, New York, United States of America.

Abstract

Granule neuron progenitors (GNPs) are the most abundant neuronal type in the cerebellum. GNP proliferation and thus cerebellar development require Sonic hedgehog (Shh) secreted from Purkinje cells. Shh signaling occurs in primary cilia originating from the mother centriole. Centrioles replicate only once during a typical cell cycle and are responsible for mitotic spindle assembly and organization. Recent studies have linked cilia function to cerebellar morphogenesis, but the role of centriole duplication in cerebellar development is not known. Here we show that centrosomal protein Cep120 is asymmetrically localized to the daughter centriole through its interaction with Talpid3 (Ta3), another centrosomal protein. Cep120 null mutant mice die in early gestation with abnormal heart looping. Inactivation of Cep120 in the central nervous system leads to both hydrocephalus, due to the loss of cilia on ependymal cells, and severe cerebellar hypoplasia, due to the failed proliferation of GNPs. The mutant GNPs lack Hedgehog pathway activity. Cell biological studies show that the loss of Cep120 results in failed centriole duplication and consequently ciliogenesis, which together underlie Cep120 mutant cerebellar hypoplasia. Thus, our study for the first time links a centrosomal protein necessary for centriole duplication to cerebellar morphogenesis.

PMID:
25251415
PMCID:
PMC4176001
DOI:
10.1371/journal.pone.0107943
[Indexed for MEDLINE]
Free PMC Article

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