The microcephaly protein Abnormal Spindle has an essential role in symmetrically dividing neural precursors to...

Neurogenesis must be coordinated in time and space to ensure proper neural development. Defects in this process can lead to a variety of brain malformations that affect tissue size and architecture. Here we examine the spatiotemporal requirements of the Abnormal Spindle (Asp) protein and its human ortholog Abnormal Spindle-Like, Microcephaly Associated (ASPM) in a fly model of human microcephaly (MCPH). By utilizing the fly optic lobe, whose neurogenic program parallels that of mammals, and the genetic tools available in this organism, we uncover the progenitor cell types and critical neurogenesis window necessary for proper brain size and architecture. Asp has an essential function in symmetrically dividing neuroepithelial precursors, yet its expression in asymmetrically dividing neuroblasts alone is not sufficient for optic lobe development. Asp is highly expressed during both embryonic and larval neurogenesis stages, but embryonic expression is dispensable for making a properly sized adult brain. We also show that Asp/ASPM's interphase nuclear localization is not required for its ability to promote brain development. Expression of the human ASPM N-terminus can also significantly rescue fly brain defects, suggesting conserved mechanisms of function in brain growth control. These results support a model where Asp expression in symmetrically dividing precursors is required to generate a sufficient pool of progenitors prior to the cell fate switch to asymmetrically dividing neuroblasts in order to generate enough neuronal cells to make a properly sized brain.