CDK5RAP2 and novel microcephaly genes in brain development

Project Leader: Angela Kaindl e-mail

 

Homozygous CDK5RAP2 gene mutations cause primary autosomal recessive microcephaly (MCPH), characterized by a severe reduction in brain volume at birth as well as mental retardation. Studying the pathogenesis of this model disorder for congenital microcephaly, we found CDK5RAP2 to be highly enriched at the centrosome of neural progenitors in mice and humans, and we identified cell-division defects in patient cells. In Cdk5rap2-downregulated mouse embryonic stem cells, we detected reduced symmetric proliferation of undifferentiated cells and even more severely reduced (asymmetric) proliferation and survival of differentiating cells. In the next funding period, we continue to investigate the mechanisms governing this cellular phenotype, in particular with respect to our hypothesis of a prominent role of CDK5RAP2 in progenitor cell differentiation. A further important goal is to identify and characterize novel microcephaly genes. We expect that insight from our analyses of patients and model systems will enable to better understand the pathomechanisms that underlie MCPH and other diseases with microcephaly.