The developmental origins and fate of neurons in the gyrencephalic neocortex

点击翻译按钮获取中文摘要

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.