Relative brain size differs considerably between species and understanding the basis of these differences is a fascinating topic in neuroscience. It is possible to identify determinants of brain size by investigating disorders that directly affect its regulation. Autosomal recessive primary microcephaly (MCPH) is characterized by an abnormally a reduction of brain growth. Current data suggests that MCPH is the result of deficient neurogenesis within the neuroepithelium of the developing cortex;disruptions to neurogenesis can result from defects in pattern formation, cell proliferation, cell survival, cell differentiation, cell migration, or cell growth. Using homozygosity mapping in inbred MCPH families, our laboratory has identified a mutation in Nucleoporin 107 (NUP107), a gene not previously linked to human disease. I propose to study this rare genetic disorder to lead to insight in human neurogenesis, causes of intellectual disability, and evolution between humans and our closest living relatives in regards to brain size and cognitive ability. I have already characterized the effect of this mutation on mRNA splicing and protein stability and have generated induced pluripotent stem cells (iPSCs) from patients and control fibroblasts;iPSCs can be used to make human neural progenitors (NPs) harboring the NUP107 mutation. Because brain size has been linked to the kinetics of neurogenesis, we would like to correlate the NUP107 mutation effects on the NP populations between mouse and human models of MCPH. To aid in the comparison of results between species, I have generated chimeric mice for a conditional NUP107 gene trap allele (NUP107GT). In this application, I propose to test the following hypotheses: 1. NUP107 mutations lead to a decrease in the number post-mitotic neurons due to a depletion of the PAX6+/SOX1+/NESTIN+ NP pool resulting in defective neurogenesis 2. NUP107 is required for apical/basal spindle orientation in differentiating (PAX6+/SOX1+/NESTIN+) NPs 3. NUP107 depletions severely affect early, symmetrical neural stem cell proliferation without a resulting defect in later, asymmetric divisions
Primary microcephaly is a neurodevelopmental disorder presumably due to altered neurogenesis and causing a great reduction in brain growth. I have identified a new causative gene, NUP107, and propose to study induced-pluripotent stem cells and knockout mice to model this human disease.