Biophysikalische Bildgebung

Identifying the genes that regulate the accurate spatiotemporal diversity of neural progenitor cells (NPCs) helps to understand the mechanisms of human neocortex expansion. In primate brains, an additional intermediate progenitor layer, the outer subventricular zone (oSVZ), facilitates the expansion of the neocortex. Here, we identify an uncharacterized gene, KIAA0408, and show that its expression is enriched in intermediate progenitors. Removing KIAA0408 in human-induced pluripotent stem cell (iPSC)-derived brain organoids results in an impaired cortical organization characterized by abnormal cell fate and patterning defects, including the depletion of intermediate and ventral progenitors. Molecularly, KIAA0408 codes for a 79-kilodalton centriolar distal appendage protein (DAP) that controls cilium biogenesis (hereafter CCB79). CCB79 forms a complex with other DAP components and specifically localizes in the DAP at the onset of ciliogenesis, and its absence blocks ciliogenesis. Mechanistically, progenitors in 3D brain tissues are unable to form cilia, which induces aberrant hedgehog signaling and causes premature differentiation. Finally, human CCB79, rather than the mouse ortholog, rescues cilia defects, suggesting that CCB79 has undergone rapid evolution from rodents to primates to fine-tune ciliogenesis for proper brain development.