Cdk5rap2 regulates centrosome function and chromosome segregation in neuronal progenitors.
Microcephaly affects approximately 1% of the population and is associated with mental retardation, motor defects and, in some cases, seizures. We analyzed the mechanisms underlying brain size determination in a mouse model of human microcephaly. The Hertwig's anemia (an) mutant shows peripheral blood cytopenias, spontaneous aneuploidy and a predisposition to hematopoietic tumors. We found that the an mutation is a genomic inversion of exon 4 of Cdk5rap2, resulting in an in-frame deletion of exon 4 from the mRNA. The finding that CDK5RAP2 human mutations cause microcephaly prompted further analysis of Cdk5rap2(an/an) mice and we demonstrated that these mice exhibit microcephaly comparable to that of the human disease, resulting from striking neurogenic defects that include proliferative and survival defects in neuronal progenitors. Cdk5rap2(an/an) neuronal precursors exit the cell cycle prematurely and many undergo apoptosis. These defects are associated with impaired mitotic progression coupled with abnormal mitotic spindle pole number and mitotic orientation. Our findings suggest that the reduction in brain size observed in humans with mutations in CDK5RAP2 is associated with impaired centrosomal function and with changes in mitotic spindle orientation during progenitor proliferation.
Lizarraga
Sofia B
SB
Division of Genetics and the Manton Center for Orphan Disease Research, Children's Hospital Boston, Howard Hughes Medical Institute, Beth Israel-Deaconess Medical Center, and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Margossian
Steven P
SP
Harris
Marian H
MH
Campagna
Dean R
DR
Han
An-Ping
AP
Blevins
Sherika
S
Mudbhary
Raksha
R
Barker
Jane E
JE
Walsh
Christopher A
CA
Fleming
Mark D
MD
D000740:Anemia / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology; D018385:Centrosome / Q000502:physiology*; D020090:Chromosome Segregation / Q000235:genetics* / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005091:Exons; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008831:Microcephaly / Q000235:genetics / Q000473:pathology; D008938:Mitosis / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000473:pathology; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D017384:Sequence Deletion; D013234:Stem Cells / Q000473:pathology
C405929:CDK5RAP2 protein, human; C549613:Cdk5rap2 protein, mouse; D018797:Cell Cycle Proteins; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger
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