Primary cilia dynamics in determining neural progenitor cell maintenance in brain development

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The primary cilium is critical for mammalian brain development. For example, its dysfunction can cause congenital microcephaly, a neurodevelopmental disorder in which the neural progenitor cell (NPC) pool is depleted. During mammalian neocortex development, the self-renewing NPCs expand their population via symmetric divisions regulated by an orchestrated cilium assembly and disassembly program. However, how NPCs accomplish timely cilium disassembly and how cilium dynamics determine NPC fate, regulate signaling, and maintain NPCs remains unknown. NPCs dynamically assemble and disassemble primary cilia, which is tightly correlated with cell-cycle exit (G1-G0) and re-entry (G1-S to M), respectively. In turn, a delay or failure in cilium disassembly acts as a brake, retaining cells in G0/G1 and transiently preventing cell cycle progression. This could be a rate-limiting step in regulating NPCs' cell cycle progression and fate in the developing brain. We hypothesize that the accurate recruitment of cilium disassembly components at the ciliary base ensures a timely cilium disassembly, which, in turn, regulates neuroepithelium development. In this project, we will first study the dynamic localization of cilium disassembly components in NPCs and manipulate them to explore the consequences of a delayed cilium disassembly on NPC fate. Second, we will dissect the altered signaling dynamics due to delayed disassembly, mainly focusing on platelet-derived growth factor (PDGF) signaling. Finally, we aim to identify how controlled cilium dynamics regulate NPC maintenance in brain tissue organization in human brain organoids. Our project will reveal molecular insights into how primary cilia dynamics control neuroepithelium organization.