Identification of novel microcephaly-linked protein ABBA that mediates cortical progenitor cell division and corticogenesis through NEDD9-RhoA

Abstract: The cerebral cortex is responsible for higher cognitive functions. Its correct development depends on coordinated asymmetric division cycles by polarized radial glial progenitor cells. Mitotic defects in neuronal stem cells are linked to the aetiology of microcephaly, but the underlying mechanisms remain incompletely understood. Here we describe a novel role of the membrane deforming cytoskeletal regulator protein Abba (MTSS1L/MTSS2) in cortical development. Loss of Abba in the developing brain resulted in radial glia proliferation arrest, disorganized radial fibers and abnormal migration of neuronal progenitors. During cell division, Abba localized to the cleavage furrow where it recruited the scaffolding protein Nedd9 and positively regulated RhoA activity. Importantly, we identified a human variant Abba (R671W) in a patient with microcephaly and intellectual disability. Ectopic expression of this mutant protein in mice phenocopied Abba knockdown. Taken together, these data provide novel mechanistic insight into human microcephaly and cortical development by identifying ABBA as a novel regulator of faithful mitotic progression of neuronal progenitor cells.