# Molecular Drivers of Human Gliogenesis

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $599,613

## Abstract

Project Summary
The formation of the central nervous system (CNS) involves a fundamental cell fate diversification—the
generation of neurons and glia. The timed, sequential appearance of neurons followed by glia is critical for
properly organizing CNS cytoarchitecture and physiology. In support of this, perturbations of the neurogenic-
to-gliogenic timer have been demonstrated in multiple neurodevelopmental disorders. Thus, an understanding
of the mechanisms that control this cell fate decision is of utmost importance.
Although the gliogenic switch is a mechanism conserved from flies to humans, the primate cortex has undergone
significant cellular and molecular evolution that has contributed to the >1000 fold increase in cortical surface
area compared to rodents. These evolutionary changes include the expansion of a unique progenitor population
called outer radial glia, along with significant changes in the molecular, functional, and morphological features
of astrocytes. These observations support the hypothesis that outer radial glia are the cellular progenitors of
human astrocytes and that this population exhibits human-specific gliogenic drivers. This proposal aims to
address two key fundamental questions about human gliogenesis: (1) In which human progenitor cell(s) does
the gliogenic switch occur, and (2) what are the intrinsic mechanisms that drive glial competence?
In this proposal, we are utilizing human iPSC-derived cortical organoids as a reductionist model system to ask
what drives human gliogenesis. The organoid model system is ideal for addressing this question because (a)
gliogenesis occurs consistently and reproducibly within a narrow temporal window, and (b) it is genetically
tractable and amenable to precise temporal studies that are not possible in other platofrms. We have developed
two aims that systematically test (Aim 1) the origins and molecular drivers of human astrogenesis, and (Aim
2) the ability of human-specific pro-glial transcription factors to initiate gliogenesis. We propose a set of
experimental approaches that will trace lineage trajectories of individual cells throughout the gliogenic swtich
and also test the mechanistic impact of impaired gliogenic drivers. We also propose a set of innovative
experiments to test distinct activation schemes of candidate transcription factors tailored to their specific
temporal and spatial binding patterns during human development.

## Key facts

- **NIH application ID:** 10459537
- **Project number:** 5R01MH125956-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Steven A Sloan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $599,613
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459537

## Citation

> US National Institutes of Health, RePORTER application 10459537, Molecular Drivers of Human Gliogenesis (5R01MH125956-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10459537. Licensed CC0.

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