CDK5RAP2 regulates centriole engagement and cohesion in mice.
Centriole duplication occurs once per cell cycle, ensuring that each cell contains two centrosomes, each containing a mother-daughter pair of tightly engaged centrioles at mitotic entry. Loss of the tight engagement between mother and daughter centrioles appears to license the next round of centriole duplication. However, the molecular mechanisms regulating this process remain largely unknown. Mutations in CDK5RAP2, which encodes a centrosomal protein, cause autosomal recessive primary microcephaly in humans. Here we show that CDK5RAP2 loss of function in mice causes centriole amplification with a preponderance of single, unpaired centrioles and increased numbers of daughter-daughter centriole pairs. These results indicate that CDK5RAP2 is required to maintain centriole engagement and cohesion, thereby restricting centriole replication. Early in mitosis, amplified centrosomes assemble multipolar spindles in CDK5RAP2 mutant cells. Moreover, both mother and daughter centrioles are amplified and the excess mother centrioles template multiple primary cilia in CDK5RAP2 mutant cells.
Barrera
Jose A
JA
Department of Pediatrics, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Kao
Ling-Rong
LR
Hammer
Robert E
RE
Seemann
Joachim
J
Fuchs
Jannon L
JL
Megraw
Timothy L
TL
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure; D016764:Cell Polarity / Q000502:physiology; D002478:Cells, Cultured; D002502:Centrioles / Q000378:metabolism* / Q000648:ultrastructure; D002923:Cilia / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008938:Mitosis / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D008941:Spindle Apparatus / Q000378:metabolism / Q000648:ultrastructure
C549613:Cdk5rap2 protein, mouse; D018797:Cell Cycle Proteins