Regulation of cellular pathways in human brain development

围产期人类中间神经元(IN)和神经胶质细胞亚型的产生和迁移以及功能整合进入神经回路的机制尚不清楚。这些过程很可能在新生儿神经损伤中被破坏，这可能导致严重的长期认知障碍以及沉重的社会和经济负担。拟议的计划将使用死后的人脑组织和啮齿动物实验系统来研究IN、OPC和小胶质细胞的发育起源、多样性和细胞相互作用。过去的主要发现包括：(I)发现出生后INS广泛迁移到专门的皮质区域，表明神经回路的形成发生在较长的一段时间(Paredes，Science；Sorrels，自然)；(Ii)HIF途径是少突胶质前体细胞(OPC)成熟的关键调节因素，低氧条件下OPC在皮质白质(袁，细胞)中形成血管生成。我们的结果表明，OPC使用血管系统作为通过发育中的大脑的交通的支架(Tsai，Science)，以及(Iii)INS在人类新生儿大脑中沿着大血管成簇迁移(Paredes，Science)。对于竞争性更新，我们在Arturo Alvarez-Buylla的指导下扩大了调查团队，以招募有前途的初级调查人员(Mercedes Paredes、Steve Fancy、Tom Nowakowski)和新的项目负责人Xian Piao。项目1调查年轻INS向人类新生儿皮质和杏仁核迁移的起源和多样性。项目2研究人类发育皮质和缺氧缺血性脑病中血管生成和IN沿血管迁移的机制。项目3将为小胶质细胞编码的GPR56途径在调节IN成熟中的作用提供证据。行政核心(A)提供预算监督、协调和获得资源。所有项目将使用由神经病理学核心(B)和转录核心(C)支持的死后新生儿神经病理标本，以支持细胞多样性的研究(VelMeshev，科学；Schirmer，自然)。这些研究旨在揭示新生儿脑损伤和先天性神经遗传性疾病影响的细胞和遗传机制。

The mechanisms that regulate the production and migration of human interneurons (IN) and glial sub-types and the functional integration into neural circuits during perinatal stages remains poorly understood. These processes are likely disrupted in neonatal neurological injuries, which can result in severe long-term cognitive disabilities and high social and financial burden. The proposed program will investigate the developmental origins, diversity and cellular interactions of IN, OPCs and microglia using post-mortem human brain tissue and rodent experimental systems. Key past findings include: (i) Discovery of extensive postnatal migration of INs to specialized cortical regions, suggesting that formation of neural circuits takes place over a protracted period (Paredes, Science; Sorrels, Nature); (ii) that the HIF pathway is a critical regulator of oligodendrocyte precursor cell (OPC) maturation and that OPCs under hypoxic conditions become angiogenic in cortical white matter (Yuen, Cell). Our results indicated that OPCs use vasculature as a scaffold to traffic through the developing brain (Tsai, Science), and (iii) that ins migrate in clusters along large vessels in human neonatal brain (Paredes, Science). For the competing renewal we have expanded the investigator team under direction of Arturo Alvarez- Buylla to recruit promising junior investigators (Mercedes Paredes, Steve Fancy, Tom Nowakowski) and new Project Leader Xian Piao. Project 1 investigates origins and diversity of migrating young INs to human newborn cortex and amygdala. Project 2 investigates the mechanisms underlying angiogenesis and IN migration along the blood vessels in human developing cortex and HIE. Project 3 will provide evidence for microglial-encoded GPR56 pathway function in regulation of IN maturation. The administrative core (A) provides budgetary oversight, coordination and access to resources. All projects will use postmortem neonatal human neuropathological specimens supported by a neuropathology core (B) and transcriptomic core (C) to support studies in cellular diversity (Velmeshev, Science; Schirmer, Nature). The studies are intended to reveal cellular and genetic mechanisms impacted by neonatal brain injury and congenital neurogenetic disease.