Developmental Timing During Cortical Development

摘要/摘要 人类大脑皮层包含了惊人的细胞类型的多样性，分布在几十个 功能区，其在早期发育过程中出现，用于明显均匀的神经上皮。长期 据推测，大脑发育异常的基因突变和与大脑发育异常有关的基因， 神经发育性精神障碍可以以多种方式影响大脑发育，但我们目前 缺乏可扩展的工具来询问它们对特化细胞类型发育的影响。 星形胶质细胞代表了一个高度多样化的细胞类别，其被广泛地分类为少数主要类型。 星形胶质细胞出现在发育后期，星形胶质细胞亚型对突变或突变的选择性脆弱性。 环境扰动可能是精神疾病或寨卡病毒感染中不同表型的基础。 然而，发育起源、分子特征和亚型特化机制尚不清楚， 明白我们目前缺乏实验方法来研究人类星形胶质细胞亚型及其发展。 我们的初步数据表明，在妊娠中期，放射状胶质细胞亚型可能偏向于产生 不同亚型的人类星形胶质细胞在建议的项目中，我们建议通过映射来扩展这一发现 放射状胶质细胞亚型在多个发育阶段的细胞分化的时间动态。 我们还将确定在雪貂中是否发生类似的发育动力学，这可以作为一种研究方法。 替代人体组织并能够进行体内功能研究。 其次，我们将确定皮质放射状胶质细胞亚型之间的发育谱系关系， 星形胶质细胞亚型我们的初步研究预测，星形胶质细胞的形态学上不同的亚型出现， 解剖学上不同的生殖器小生境，我们建议直接注册这些形态类型的转录组学 使用单细胞mRNA测序进行鉴定。 最后，我们的目标是了解不同的放射状胶质细胞亚型是否有助于不同的细胞类型， 大脑皮层为了解决这个问题，我们建议进行异种移植实验到小鼠， 个脑袋我们将联合收割机与单细胞测序和计算机分析结合起来，共同嵌入我们的数据 与现有的成人大脑皮层资源，揭示什么分子亚型可能出现， 转录组学上不同的皮质祖细胞亚型。

Summary/Abstract The human cerebral cortex contains an astonishing diversity of cell types distributed across dozens of functional areas, which emerge during early development for an apparently uniform neuroepithelium. It has long been hypothesized that genetic mutations underlying brain development abnormalities and genes implicated in neurodevelopmental psychiatric disorders can impact brain development in a variety of ways, but we currently lack scalable tools for interrogating their impact on the development of specialized cell types. Astrocytes represent a highly diverse cell class that is broadly categorized into a handful of cardinal types. Astrocytes emerge in late development, and selective vulnerabilities of astrocyte subtypes to mutations or environmental perturbations may underlie distinct phenotypes in psychiatric disorders or in Zika virus infection. However, developmental origins, molecular characteristics, and mechanisms of subtype specification are poorly understood. We currently lack experimental methods to study human astrocyte subtypes and their development. Our preliminary data suggest that at mid-gestation, radial glia subtypes may be biased towards generating different subtypes of human astrocytes. In the proposed project we propose to extend this finding by mapping the temporal dynamics of cellular differentiation from radial glia subtypes across multiple stages of development. We will also determine whether similar developmental dynamics take place in ferret, which could serve as a substitute to human tissue and enable in vivo functional studies. Secondly, we will determine developmental lineage relationships between cortical radial glia subtypes and astrocyte subtypes. Our preliminary studies predict morphologically distinct subtypes of astrocytes emerge from anatomically distinct germinal niches, and we propose to directly register these morphotypes to transcriptomic identities using single cell mRNA sequencing. Finally, our goal is to understand whether distinct radial glia subtypes contribute distinct cell types of the cerebral cortex. To address this question, we propose to perform xenotransplantation experiments into mouse brain. We will combine this approach with single cell sequencing, and in silico analyses co-embedding our data with existing resources from adult human cortex to reveal what molecular subtypes may emerge from transcriptomically- distinct subtypes of cortical progenitor cells.