Abstract
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. We found that Asp expression in symmetrically dividing neuroepithelial precursors can promote proper optic lobe development, while expression in asymmetrically dividing neuroblasts cannot. Further, we show that Asp expression during the larval neurogenesis stage is sufficient for making a properly sized adult brain. We also show that Asp and ASPM's interphase nuclear localization is not required for their ability to promote brain development. Finally, expression of the human ASPM N-terminus can also significantly rescue fly optic lobe size, 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.
