Cdk5rap2 interacts with pericentrin to maintain the neural progenitor pool in the developing neocortex.
Primary autosomal-recessive microcephaly (MCPH) and Majewski osteodysplastic primordial dwarfism type II (MOPDII) are both genetic diseases that result in decreased brain size at birth. MCPH is thought to arise from alterations in the size of the neural progenitor pool, but the cause of this defect has not been thoroughly explored. We find that one of the genes associated with MCPH, Cdk5rap2, is highly expressed in the neural progenitor pool and that its loss results in a depletion of apical progenitors and increased cell-cycle exit leading to premature neuronal differentiation. We link Cdk5rap2 function to the pericentriolar material protein pericentrin, loss of function of which is associated with MOPDII. Depletion of pericentrin in neural progenitors phenocopies effects of Cdk5rap2 knockdown and results in decreased recruitment of Cdk5rap2 to the centrosome. Our findings uncover a common mechanism, involving aberrations in the neurogenesis program, that may underlie the development of microcephaly in multiple diseases.
Buchman
Joshua J
JJ
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 46, Room 4235A, Cambridge, MA 02139, USA.
Tseng
Huan-Chung
HC
Zhou
Ying
Y
Frank
Christopher L
CL
Xie
Zhigang
Z
Tsai
Li-Huei
LH
D000704:Analysis of Variance; D000818:Animals; D000941:Antigens / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D019579:Neocortex / Q000254:growth & development / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D034622:RNA Interference
D000941:Antigens; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C086178:pericentrin