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

原代纤毛动力学决定大脑发育中神经祖细胞的维持

• 批准号: 529712929
• 负责人: Professor Dr. Jay Gopalakrishnan, Ph.D.
• 金额: --
• 依托单位: Labor für Zentrosomen- und Zytoskelettbiologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/529712929?language=en
• 关键词: Primary; cilia; dynamics; determining; neural

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.

初级纤毛是哺乳动物大脑发育的关键。例如，它的功能障碍可能导致先天性小头畸形，这是一种神经发育障碍，神经前体细胞(NPC)池耗尽。在哺乳动物的新皮质发育期间，自我更新的NPC通过对称的分裂来扩大它们的种群，这些对称分裂受到编排的纤毛组装和拆解程序的调节。然而，鼻咽癌如何完成及时的纤毛分解以及纤毛动力学如何决定鼻咽癌的命运、调节信号和维持鼻咽癌仍然是未知的。原生纤毛的动态组装和拆解分别与细胞周期退出(G1-G0)和重新进入(G1-S至M)密切相关。反过来，纤毛分解的延迟或失败起到刹车的作用，将细胞保留在G0/G1期，并暂时阻止细胞周期的进展。这可能是调控鼻咽癌细胞周期进程和发育中大脑命运的限速步骤。我们假设纤毛分解组分在纤毛底部的准确募集确保了纤毛的及时分解，而纤毛分解反过来又调节了神经上皮的发育。在本项目中，我们将首先研究纤毛分解组件在鼻咽癌中的动态定位，并对其进行操纵，以探索纤毛分解延迟对鼻咽癌命运的影响。其次，我们将剖析延迟拆解引起的信号动力学变化，主要集中在血小板衍生生长因子(PDGF)信号转导上。最后，我们的目标是确定受控纤毛动力学如何在人脑器官中调节脑组织中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洞察力。