# Cellular and Molecular Mechanisms of Corticogenesis

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $506,512

## Abstract

PROJECT SUMMARY
Prenatal or neonatal exposure to drugs of abuse such as cocaine and ethanol has been shown to disrupt
neurogenesis and/or gliogenesis in the developing cerebral cortex, and induce functional abnormalities late in
life. Proper formation of the cortex depends on the orderly production of a large number of diverse neurons, as
well as glial cells. Radial glial cells have been shown to be a predominant population of neural progenitor cells
in the developing cortex. In addition to their well-characterized role in supporting neuronal migration, radial glial
progenitors (RGPs) actively divide to proliferate and to generate neurons and glial cells either directly or
indirectly. The division mode and dynamics of RGPs essentially determine the number and types of neurons
and glia in the cortex; however, the precise behavior and lineage progression of RGPs and the underlying
molecular regulation are poorly understood. The long-term goal of this project is to systematically delineate
RGP behavior and progeny output at the cellular and molecular levels. RGPs are neither synchronized in
division dynamics nor homogenous in division pattern and progeny output. This calls for a systematic and
quantitative analysis of the precise mitotic behavior and progeny output of RGPs in vivo at the single cell
resolution. Recently, we exploited the unprecedented resolution of mosaic analysis with double markers
(MADM) on progenitor division and progeny output, and performed a systematic and quantitative clonal
analysis of RGP division and lineage progression. We revealed, for the first time, that RGPs progress through
a remarkably deterministic and orderly program in proliferation, neurogenesis, and gliogenesis. Based on
strong published and preliminary data, the central hypothesis of this application is that the behavior and output
of individual RGPs are highly programmed at the cellular and molecular levels to produce a correct number
and type of neurons and glia in the cortex. This hypothesis will be tested by 1) systematically and quantitatively
examine the number, type, and organization of astrocytes and/or oligodendrocytes generated by individual
RGPs at different embryonic stages using MADM, and 2) elucidate the molecular programs that regulate RGP
lineage progression in proliferation, neurogenesis, and gliogenesis by performing in-depth real time single-cell
transcriptome analysis of RGPs across different embryonic stages using CEL-seq in conjunction with loss-of-
function studies using mouse genetics and/or CRISPR/CAS9 approaches. By integrating a battery of cutting-
edge techniques, the proposed research will provide fundamental new molecular and cellular insights into RGP
behavior and cortical neurogenesis and gliogenesis. This contribution will be significant because it will not only
advance the basic knowledge of cortical histogenesis, but will also expand our understanding of the underlying
cause of drugs of abuse-induced brain damage or other de...

## Key facts

- **NIH application ID:** 9977142
- **Project number:** 5R01DA024681-13
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** ALEXANDRA L. JOYNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $506,512
- **Award type:** 5
- **Project period:** 2008-07-15 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977142

## Citation

> US National Institutes of Health, RePORTER application 9977142, Cellular and Molecular Mechanisms of Corticogenesis (5R01DA024681-13). Retrieved via AI Analytics 2026-05-31 from https://api.ai-analytics.org/grant/nih/9977142. Licensed CC0.

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