Cerebral cortical development is a highly orchestrated process, with production of neurons destined for the cortical layers produced in order, deep to superficial, followed by glial generation. The timing of this process is very different between species. For example, mouse corticogenesis occurs over approximately a week of gestation, while in humans the process takes several months, resulting in a much larger and more complex cortex. Lineage studies have functionally defined the major types of neural progenitor cells (NPCs) contributing to corticogenesis, including stem cell-like radial glial cells (RGCs) and intermediate progenitor cells (IPCs). However, much remains to be discovered regarding how RGCs and IPCs are specified over time. We have discovered that during asymmetric RGC-IPC cell divisions, the RNA binding protein Stau2 segregates a complex cargo of coding and non-coding RNA specifically into the IPC daughter. Analysis of this cargo at different embryonic stages by RNA-sequencing has revealed networks of genes that are candidates for controlling proliferation and temporal specification of the IPC fate. Here we propose to test these candidates in functional studies, using high-throughput automated time-lapse image analysis for in vitro studies, as well as a novel lentiviral in vivo screening method, to define their roles in specifying IPCs and timing corticogenesis. In contrast to the progress made in understanding the characteristics of mouse cortical progenitor cells, less is understood regarding human cortical progenitors. Fundamental knowledge about how human RGCs and IPCs produce diverse progeny over time, their division mode, cell cycle times and lineages, remains unknown. Here we will address these gaps in knowledge using long-term time-lapse lineage analysis in vitro. In addition, by identifying genes expressed in human cortical progenitor cells, including at the single cell level and via analysis of the Stau2 cargo, we will reveal human cortical progenitor subtypes and heterogeneity. Further, a comparison of human and mouse cortical progenitor cell data will help illuminate key differences to address a major mystery: the difference in timing of mouse and human cortical development. Our lab continues to explore the interaction of environmental factors on cortical progenitor cells, aided by the ability to rapidly quantify changes in proliferation, division mode and differentiation using time-lapse analysis. Soluble factors released by structures in the germinal niche such as vascular endothelial cells and the choroid plexus, act on cortical progenitors to regulate the numbers and types of progeny they produce. Our recent work has identified a panel of candidate niche molecules secreted by the choroid plexus that could interact with receptors expressed on neural progenitors, which we propose to examine in vitro and in vivo, in mouse and human. Defining niche factors and their specific actions paves the way to address diseases that involve degeneration of stem cell zones which are normally active throughout life. Furthermore, defining environmental factors that act on human NPCs is important for translation towards regenerative therapy development.

Public Health Relevance

The cerebral cortex develops from embryonic cells that divide and differentiate to produce the diverse sets of neurons and glia that constitute the adult cortical architecture. This process is tightly regulated over time so that the cortex is built in an orderly manner, which is essential to achieve normal function. Here we propose to identify and study genes that regulate the production of different cortical cells over time. We will carry out this work in mouse and in human using stem cell technology, which has the potential to reveal new knowledge about how the human cortex forms, and how neural stem cells can be activated to counteract developmental and neurodegenerative disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Unknown (R35)
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Special Emphasis Panel (ZNS1)
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Lavaute, Timothy M
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Regenerative Research Foundation
United States
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