The developmental origins and fate of neurons in the gyrencephalic neocortex

摘要/摘要： 神经元和胶质细胞的不同网络产生了哺乳动物大脑的高级计算能力。 脑室和室下区(VZ和SVZ)存在神经前体细胞(NPC)群。 胎儿期大脑直接或间接通过中间祖细胞产生所有神经元和神经胶质细胞。在那里的时候 对这些细胞的多样性和潜在的遗传机制的了解迅速增加 前体细胞，这项工作的大部分已经在后脑啮齿动物身上完成。的一些最新发现 脑回物种提示鼻咽癌类型及其发育机制在 大脑更大的物种。例如，最近的研究发现，与啮齿动物不同的是， 基底径向胶质细胞(BRGCs)在灵长类动物脑中显著较高，但神经解剖学和 这种差异的神经生理学优势(S)还没有确立。同样，大量的 迁移到额叶的神经元存在于人类婴儿的大脑中，但在小鼠中没有；两者都不存在 它们在出生前产生的机制或整合到新皮质的过程有 已被确认身份。虽然单细胞转录数据为基因表达打开了新的窗口 在这种多样性的背后，不仅有能力确认特定物种的差异，而且有能力询问他们的 由于缺乏合适的模型，体内的影响受到阻碍。小猪是一个强大的研究模型 复杂的大脑发育，因为它们有高度进化的脑回新皮质。我们之前的研究 发现猪SVZ的细胞结构与人类SVZ的细胞结构异常相似。一致 随着人类婴儿皮质的出现，仔猪SVZ中的年轻神经元迁移到额叶皮质，并分化为 神经元以特定于区域的方式。最后，我们最近的合作单细胞测序研究揭示了 在仔猪SVZ内具有在啮齿动物SVZ中没有的独特分子特征的细胞群体。因此，我们 阐明猪VZ和SVZ神经前体的多样性和命运潜力的假设将 加快我们对人类神经元多样性、大脑皮层回路复杂性和认知能力的理解。我们的 该项目将建立一种体内基因传递方法，以可视化鼻咽癌动力学和神经元规范 胚胎仔猪VZ和SVZ(目标1)；并可视化来自 生后仔猪SVZ(目标2)。大脑回脑研究系统的建立 使用现代遗传和细胞成像技术将极大地影响我们对正常 人脑发育，为阐明神经发育的病因学提供了重要工具 精神错乱。这一进展将使关键的比较研究与其他数据集从脑回和 无脑物种，并允许基因组/细胞理解早期大脑发育的模型中 在发育和解剖学上与人脑有重要的相似之处。

SUMMARY/ABSTRACT: Diverse networks of neurons and glia produce the advanced computational power of the mammalian brain. Neural precursor cell (NPC) populations present in the ventricular and subventricular zones (VZ and SVZ) of the prenatal brain generate all neurons and glia either directly, or indirectly via intermediate progenitors. While there has been a rapid increase in understanding the cell diversity and underlying genetic mechanisms of these precursor cells, most of this work has been accomplished in the lissencephalic rodent. Some recent findings in gyrencephalic species indicate that NPC types and their developmental mechanisms are tuned differently in species with larger brains. For example, recent studies have discovered that, unlike in rodents, the density of basal radial glial cells (bRGCs) is significantly higher in primate brain, but the neuroanatomical and neurophysiological advantage(s) of this difference have not been established. Similarly, large numbers of neurons migrating to the frontal lobe are present in the human infant brain but are not found in mouse; neither the mechanisms underlying their prenatal generation nor their processes of integration into the neocortex have been identified. While single cell transcriptomic data has opened new windows into the gene expression underlying this diversity, the ability to not only confirm species-specific differences but to also interrogate their effects in vivo is hampered by the lack of an appropriate model. Piglets are a powerful model with which to study complex brain development because they have a highly evolved gyrencephalic neocortex. Our previous studies found that the cytoarchitecture of the porcine SVZ is exceptionally similar to its human counterpart. Consistent with the human infant cortex, young neurons in the piglet SVZ migrate to the frontal cortex and differentiate into neurons in a region-specific manner. Finally, our recent collaborative single cell sequencing study has uncovered cell populations with unique molecular profiles within the piglet SVZ that are not found in rodent SVZ. Thus, we hypothesize that elucidating the diversity and fate potential of the porcine VZ and SVZ neural precursors will accelerate our understanding of human neuronal diversity, cortical circuit complexity and cognitive ability. Our project will establish an in vivo gene delivery method to visualize NPC dynamics and neuronal specification in the fetal piglet VZ and SVZ (Aim 1); and visualize late-migrating neurons and cell populations derived from the postnatal piglet SVZ (Aim 2). Establishment of a system in which a large gyrencephalic brain can be studied using modern genetic and cellular imaging techniques would significantly impact our understanding of normal human brain development and provide a critical tool for elucidating the etiology for neurodevelopmental disorders. This advance will enable key comparative studies with other datasets from gyrencephalic and lissencephalic species and allow genomic/cellular understanding of early brain development in a model that shares important developmental and anatomical similarities to the human brain.