The microcephaly gene ASPM is required for the timely generation of human outer-radial glia progenitors by controlling mitotic spindle orientation

Abnormal spindle-like, microcephaly-associated (ASPM) is the most commonly mutated gene in primary microcephaly (MCPH), characterized by reduced brain size and intellectual deficiency. The mechanisms underlying MCPH have remained unclear, as ASPM disruption leads to distinct phenotypes depending on the species studied. Here, we studied the impact of ASPM pathogenic mutations on human corticogenesis in organoid models. We found that at earliest stages of neurogenesis, ASPM mutant cortical progenitors, located at the apical surface of the neuroepithelium, display transient mitotic spindle randomization. The mutant progenitors then delaminate basally to adopt precociously the characteristics of outer radial glia cells (oRGC), a population of progenitors selectively amplified in human corticogenesis. Subsequently, cortical progenitors are depleted through decreased amplification and increased apoptosis. Thus, ASPM regulates the timely generation of oRGC by controlling mitotic spindle orientation, shedding light on how species-specific features of neurogenesis may confer vulnerability to neurodevelopmental diseases.