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

初级纤毛对哺乳动物的大脑发育至关重要。例如，它的功能障碍可导致先天性小头畸形，这是一种神经发育障碍，其中神经祖细胞（NPC）池耗尽。在哺乳动物新皮层发育过程中，自我更新的npc通过纤毛组装和拆卸程序调节的对称分裂来扩大其种群。然而，NPC如何完成及时的纤毛拆卸，以及纤毛动力学如何决定NPC的命运、调节信号和维持NPC仍然未知。npc动态组装和拆卸初级纤毛，它们分别与细胞周期退出（G1-G0）和再进入（G1-S至M）密切相关。反过来，纤毛拆卸的延迟或失败起到了刹车的作用，使细胞保持在G0/G1状态，并暂时阻止细胞周期的进展。这可能是调节npc细胞周期进程和发育中的大脑命运的限速步骤。我们假设纤毛基部的纤毛拆卸成分的准确募集确保了纤毛的及时拆卸，这反过来调节了神经上皮的发育。在这个项目中，我们将首先研究NPC中纤毛拆卸组件的动态定位，并操纵它们来探索纤毛拆卸延迟对NPC命运的影响。其次，我们将剖析由于延迟分解而改变的信号动力学，主要关注血小板衍生生长因子（PDGF）信号。最后，我们的目标是确定受控制的纤毛动力学如何调节人脑类器官脑组织中NPC的维持。我们的项目将揭示初级纤毛动力学如何控制神经上皮组织的分子见解。

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.