# Understanding glial fate restriction in humans

> **NIH NIH R01** · HARVARD UNIVERSITY · 2024 · $754,617

## Abstract

Abstract
This proposal aims to determine the mechanisms that lead to the generation of astrocytes in the developing
human cortex. Astrocytes are the most abundant cell type in the adult human brain, mediating vital functions
including myelination, axonal guidance, synaptogenesis, and maintenance of the blood-brain barrier. During
development, control over the spatio-temporal patterns of the production and numbers of astrocytes is necessary
for proper brain function. The developmental potential of neocortical progenitors exhibits evolutionary divergence
across mammalian clades, leading to primate-specific cell types, such as interlaminar astrocytes. Progress in
studying human astrocytic development is limited by the ethical and practical challenges in working with human
fetal tissue and fundamental differences between mammalian models and humans. Consequently, how the
developmental potential of progenitor cells of the cortex is restricted to generate astrocytes remains unknown.
Addressing this question is essential for understanding human brain development and will lay the foundation for
uncovering the causes and devising new treatment strategies for astrocyte-related human diseases
In mouse, astrocytic progenitors arise only after cortical neurons from the six layers are generated. The common
hypothesis was that, similarly, astrocytes arise from outer radial glia in humans in the second trimester of
development after the layers of the cortex are already formed. Preliminary work obtained through the analysis of
single-cell gene expression data from the developing human cortex, in vitro embryonic stem cell experiments,
and in vitro to in vivo mapping shows that the astrocytic lineage in humans arises very early before the cortical
layers are formed and likely from the neuroepithelium of the forebrain. Computational analysis of the fetal tissue
single-cell expression data and preliminary experiments implicate cell-to-cell contact-dependent signaling
through YAP and NOTCH pathways in determining the astrogliogenic fate of the progenitors. Further, preliminary
computational analyses of human fetal data identify critical transcription factors involved in this fate decision.
The proposal aims to determine the developmental potential and the lineage decisions of the newly identified
astrogliogenic progenitors over 9 months. This will be accomplished by tracing the lineage decisions of
progenitors in the validated in vitro system using viral bar-coded viral libraries and clonal analyses and mapping
the results, through data analysis, onto in vivo human fetal data as well as through immunostaining of
cryosectioned fetal tissue obtained at different time points.
The proposal further aims to determine the role of YAP and NOTCH signaling and the computationally implicated
transcription factors in generating these newly identified progenitors. This is accomplished through novel human
embryonic stem cell lines and live imaging to monitor the dynamics of these s...

## Key facts

- **NIH application ID:** 10979956
- **Project number:** 1R01MH134993-01A1
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Sharad Ramanathan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $754,617
- **Award type:** 1
- **Project period:** 2024-07-05 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979956

## Citation

> US National Institutes of Health, RePORTER application 10979956, Understanding glial fate restriction in humans (1R01MH134993-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10979956. Licensed CC0.

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