Developmental Timing During Cortical Development

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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.