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

The cerebral cortex, which is responsible for higher cognitive functions, relies on the coordinated asymmetric division cycles of polarized radial glial progenitor cells for proper development. Defects in the mitotic process of neuronal stem cells have been linked to the underlying causes of microcephaly; however, the exact mechanisms involved are not fully understood. In this study, we present a new discovery regarding the role of the membrane-deforming cytoskeletal regulator protein called Abba (also known as MTSS1L/MTSS2) in cortical development. When Abba was absent in the developing brain, it led to a halt in radial glial cell proliferation, 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 influenced the activity of RhoA, a crucial regulator of cell division. Notably, we identified a variant of Abba (R671W) in a patient with microcephaly and intellectual disability, further highlighting its significance. The introduction of this mutant Abba protein in mice resulted in phenotypic similarities to the effects of Abba knockdown. Overall, these findings offer valuable mechanistic insights into the development of microcephaly and the cerebral cortex by identifying Abba as a novel regulator involved in ensuring the accurate progression of mitosis in neuronal progenitor cells.