CDK5RAP2 Regulates Centriole Licensing to Restrict Centriole Duplication in Mice




Barrera, Jose Anselmo

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Cells division is a highly coordinated series of events that must occur with extreme precision. Defects during segregation of genetic material (DNA) can have adverse effects on the health of the cell, surrounding tissue, organ, and the organism as a whole. Accurate assembly of the bipolar mitotic spindle apparatus is crucial for precise chromosome segregation. Centrosomes play a crucial role in establishment of the mitotic spindle and therefore are vital to the maintenance of genetic stability. Centrosomes are composed of two centrioles that arrange a specialized conglomerate of proteins into a pericentriolar matrix. Centrosomes are highly regulated throughout the cell cycle, and duplicate only once per cell cycle ensuring that each cell inherits one centrosome after mitotic exit, and contains only two centrosomes at the following mitosis. Truncating mutations in the Cyclin-Dependent Kinase 5 Regulatory Associated Protein 2 gene (CDK5RAP2), which encodes a centrosomal protein, result in autosomal recessive primary microcephaly (MCPH, [MIM 251200]) in humans. The major phenotypic manifestation of this rare genetic disorder is a small head. Affected individuals have head circumferences at least 4 standard deviations below sex- and age-matched individuals and suffer mental retardation. In order to investigate how mutations in CDK5RAP2 affect centrosome structure and regulation, and how this leads to MCPH, we derived two distinct mouse mutant lines with truncating mutations within the CDK5RAP2 locus similar to those found in affected humans. We show that centriole engagement and cohesion, two distinct centriole-binding processes, are disrupted in CDK5RAP2 mutant cells. Partial disruption of CDK5RAP2 affected centriole cohesion, whereas complete CDK5RAP2 disruption deregulated the centriole duplication cycle leading to centriole/centrosome amplification. During mitosis amplified centrosomes in CDK5RAP2 mutant cells were potent microtubule organizing centers that drove formation of multipolar spindles. Furthermore, cells formed multiple primary cilia from multiple centrioles inherited from the previous cell cycle. Together these results define a role for CDK5RAP2 in the regulation of centriole duplication and also provide a basis for the development of MCPH.

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