Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication

Abstract

Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. Thus, centriolar satellites build a MCPH complex critical for human neurodevelopment that promotes CDK2 centrosomal localization and centriole duplication.

DOI: http://dx.doi.org/10.7554/eLife.07519.001

eLife digest

When a cell divides, the chromosomes that contain the genetic blueprint for the cell must be replicated and shared between the two new cells. A structure called the centrosome organizes the cellular machinery that separates the chromosome copies during cell division. At the center of each centrosome are two cylindrical microtubule-based structures called centrioles.

Mutations in certain proteins that interact with the centrosome cause a neurodevelopmental disorder called primary microcephaly. People born with microcephaly have unusually small heads and brains. As a result, they may have difficulties with mental tasks. Scientists do not know exactly how these ‘microcephaly-associated’ proteins normally interact with the centrosomes or what they do at the centrosomes, so it is difficult to work out what goes wrong in people with microcephaly. One idea is that the proteins help to duplicate the centrioles before a cell divides. If this duplication does not occur, a cell cannot divide properly; so, people with mutations that interfere with centriole duplication cannot grow enough brain cells.

Now, Kodani et al. have examined how these microcephaly-associated proteins work with ‘satellite’ proteins that congregate near the centrosome to duplicate centrioles. The satellite proteins help to recruit four microcephaly-associated proteins to the centrosome, where they are built into a ring. The microcephaly-associated proteins congregate at the centrosome in a particular order, with each protein recruiting the next one in the sequence. Once all four are in place near the centrosome, an enzyme that helps to duplicate the centrioles joins them.

Further experiments suggest that mutations that affect one of the satellite proteins—known as CEP90—may cause microcephaly. Future analysis of how microcephaly-associated genes work may reveal the cell biological mechanisms by which centrioles participate in brain development.

DOI: http://dx.doi.org/10.7554/eLife.07519.002