Identification and Characterization of Genes Essential for Human Brain Development

The human brain is a network of ninety billion neurons that allows for many of the behavioral adaptations considered unique to our species. One-fifth of these neurons are layered in an epithelial sheet known as the cerebral cortex, which is exquisitely folded into convolutions called gyri. Defects in neuronal number clinically present with microcephaly (Greek for “small head”), and in inherited cases these defects can be linked to mutations that identify genes essential for neural progenitor proliferation. Most microcephaly genes are characterized to play a role in the centrosome, however rarer presentations of microcephaly have identified different mechanisms. Charged multivesicular body protein/Chromatin modifying protein 1A (CHMP1A) is a member of the ESCRT-III endosomal sorting complex, but is also suggested to localize to the nuclear matrix and regulate chromatin. We show that loss-of-function mutations to human CHMP1A cause a rare microcephaly syndrome with reduced cerebellar volume. CHMP1A mutant cells show impaired proliferation, with increased expression of INK4A, a negative regulator of stem cell proliferation, and loss of enrichment of INK4A promoter DNA in chromatin immunoprecipitations performed against BMI1, indicating a loss of the normal repression of INK4A by BMI1. Defects in zebrafish produced by morpholino-based knockdown of the CHMP1A orthologue resembled those seen after bmi1 knockdown, and were partially