The neural network architecture of the mammalian neocortex is constructed from diverse neuronal cell types. Understanding the developmental origins of these cell types is prerequisite for exploring how they assemble the intricate, yet stereotyped circuits that guide intelligent behavior. Glutamatergic pyramidal neurons (PyNs) constitute ~80% of cortical neurons and are defined by their laminar locations, axon projections, physiology, and gene expression. Diverse PyNs form multiple local subnetworks, inter-areal processing streams, and distinct cortical output channels that subserve motor, cognitive and emotional functions. However, the developmental origins of the diversity of PyN subtypes are not well understood. The progenitor cells that give rise to PyNs mainly include radial glial cells (RGCs) and intermediate progenitor cells (IPCs) located in the embryonic cerebral ventricle wall. RGCs divide asymmetrically to generate neurons either directly or indirectly through IPCs, which divide symmetrically to produce pairs of PyNs. It remains unclear how progenitor types (e.g. RGCs, IPCs), their lineage progression, and timing of neurogenesis contribute to the specification of diverse PyN subtypes defined by axon projection, connectivity, and physiology. In particular, the role of IPCs in the generation of PyNs is poorly understood. The T-domain transcription factor (Tbr2) is specifically expressed in cortical IPCs. We have generated an inducible Tbr2-CreER mouse driver, which allows comprehensive lineage tracing from IPCs. I have developed a novel genetic method to fate-map neurons not only according to their lineage, but by precise birth time. We will assay fate-mapped PyNs in terms of axon projection. The goal of this proposal is to combine these state-of-the-art genetic tools to examine the role of IPCs in the specification of PyN subtypes. IPCs are crucial for cortical development, especially in the generation of upper layer PyN subtypes that constitute processing streams linking functionally related cortical areas. Understanding their role is a key step toward elucidating how their dysfunction contributes to a range of neurodevelopmental disorders, including autism spectrum disorders.
This proposal is concerned with studying an aspect of neurodevelopment that has broad implications for understanding how normal developmental processes can be disrupted in neuropsychiatric disorders. I am investigating the development of pyramidal neurons, which are the majority of neurons in the neocortex and are the building blocks of the information processing streams that generate neural output and, as such, they are likely involved in many neurological disorders. Specifically, mutations in the gene this proposal focuses on, Tbr2, are known to result in defects in neural development in humans, including microcephaly, polymicrogyria, corpus callosum agenesis, and intellectual disability.
