Developmental Timing During Cortical Development

摘要/摘要 人类大脑皮层包含了惊人的多样性的细胞类型，分布在数十个 功能区，在早期发育过程中形成明显统一的神经上皮。它已经有很长时间了 曾假设大脑发育异常背后的基因突变和与 神经发育性精神障碍可以通过各种方式影响大脑发育，但我们目前 缺乏可扩展的工具来调查它们对特殊细胞类型发展的影响。 星形胶质细胞代表了一个高度多样化的细胞类别，被广泛地归类为几种基本类型。 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 环境干扰可能是精神障碍或寨卡病毒感染的不同表型的基础。 然而，亚型指定的发育起源、分子特征和机制研究较少。 明白了。我们目前缺乏研究人类星形胶质细胞亚型及其发育的实验方法。 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 人类星形胶质细胞的不同亚型。在提议的项目中，我们建议通过绘制地图来扩展这一发现 多个发育阶段放射状胶质细胞亚型细胞分化的时间动力学。 我们还将确定类似的发育动态是否发生在雪貂身上，这可能是一种 替代人体组织，使体内功能研究成为可能。 其次，我们将确定皮质放射状胶质细胞亚型和 星形胶质细胞亚型。我们的初步研究预测，在形态上不同的亚型星形胶质细胞将从 在解剖学上截然不同的生发生态位，我们建议将这些形态类型直接注册到转录 用单细胞信使核糖核酸测序鉴定。 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，我们建议对小鼠进行异种移植实验。 大脑。我们将把这种方法与单细胞测序相结合，并在电子计算机分析中共同嵌入我们的数据 利用来自成人大脑皮质的现有资源来揭示可能出现的分子亚型 转录上不同亚型的皮质祖细胞。

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.