Intermediate neuronal progenitors in neocortical development

描述（由申请人提供）：中间神经源性祖细胞（INPs）是一种相对“新”类型的新皮质祖细胞，其性质、子神经元命运和在神经发生调节中的功能仍不清楚。本计画将描述INPs的分子和细胞特性，定义其对皮质区域和层的贡献，并研究INPs受内在和外在因素的调控。这个问题的核心假设是 INPs不仅调节整体神经发生，而且还调节神经元分化的更微妙方面，如区域身份和层命运。这些研究将使用各种小鼠等位基因完成，包括一种新的遗传谱系追踪系统，以识别来自INP队列的皮质神经元。本项目的第一个目的是表征INP转录组，并定义INP的增殖和克隆特性。第二个目的是确定INP子代神经元对皮质区域、层和细胞类型的贡献。第三个目的是确定Eomes，一种在INPs中特异性表达的转录因子，如何调节INPs的分子和发育特性。第四个目的是确定成纤维细胞生长因子信号传导如何影响INP增殖和分化。总之，这些集中的研究将提供一个连贯的理解INPs，他们在皮质生成的作用，以及他们可能的贡献，神经发育障碍和治疗。最终，我们对自闭症和智力残疾等疾病的理解将得到提高，我们更好地诊断和治疗这些疾病的能力也将提高。

DESCRIPTION (provided by applicant): Intermediate neurogenic progenitors (INPs) are a relatively "new" type of neocortical progenitor cells whose properties, daughter neuron fates, and functions in the regulation of neurogenesis remain unclear. This project will characterize molecular and cellular properties of INPs, define their contribution to cortical areas and layers, and study the regulation of INPs by intrinsic and extrinsic factors. The central hypothesis of this project is that INPs regulate not only overall neurogenesis, but also more subtle aspects of neuron differentiation such as regional identity and laminar fate. These studies will be accomplished using a variety of mouse alleles, including a novel genetic lineage tracing system to identify cortical neurons derived from INP cohorts. The first Aim of this project is to characterize the INP transcriptome, and define proliferative and clonal properties of INPs. The second Aim is to determine the contribution of INP daughter neurons to cortical areas, layers, and cell types. The third Aim is to determine how Eomes, a transcription factor that is specifically expressed in INPs, regulates molecular and developmental properties of INPs. The fourth Aim is to determine how fibroblast growth factor signaling affects INP proliferation and differentiation. Together, these focused studies will provide a coherent understanding of INPs, their roles in corticogenesis, and their possible contributions to neurodevelopmental disorders and therapies. Ultimately, our understanding of diseases such as autism and intellectual disability will be advanced, as will our ability to better diagnose and treat these disorders.