# Mechanisms of Oligodendrocyte Fate Specification in the Developing Neocortex

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $329,473

## Abstract

PROJECT SUMMARY
The neocortex is crucial for execution of our higher order brain functions such as cognition, consciousness,
perception and motor control. The complex neural circuits that underlie these functions are built from many
different types of neurons and glia during brain development. How this cell type diversity is achieved from a
common pool of neural progenitors in the developing forebrain is a major research focus, but there are still
many fundamental gaps in our knowledge of this process. In particular, the molecular mechanisms that control
glial cell fate specification and generation from neocortical progenitors are largely unexplored. The long-term
goal of this project is to understand the mechanisms underlying cell type diversity and specification in the
cerebral cortex and to use this knowledge for therapeutic purposes in the diseased brain. The objective of this
proposal is to elucidate the mechanisms underlying oligodendrocyte specification and subtype diversity.
Oligodendrocytes are essential for normal brain development and function, and their importance is
underscored in diseases in which they are disrupted, including multiple sclerosis and leukodystrophies. Similar
to neurons, recent studies have started to uncover diversity within the oligodendrocyte lineage that likely
reflects their multiple functions in the neocortical circuitry. The early developmental origins of this
oligodendrocyte diversity are not known. Preliminary data produced in the applicants' laboratory indicates that
1) oligodendrocyte lineage specification from neural progenitors begins early in neocortical development,
before neurogenesis is complete; 2) Sonic hedgehog signaling to progenitors in the embryonic dorsal forebrain
is critical for generating neocortical oligodendrocytes; and 3) heterogeneity within the neocortical
oligodendrocyte lineage depends on precise regulation of Sonic hedgehog signaling levels. Based on these
data, the central hypothesis is that embryonic Shh signaling restricts a subset of neocortical progenitors to
oligodendrocyte identities, and differing levels of Shh signaling further specifies subtype fate within the
oligodendrocyte lineage. This hypothesis will be tested by pursuing two specific aims using in vivo techniques
in mice: 1) Under the first aim, daughter cells belonging to the dorsal Ascl1 lineage will be identified by genetic
fate-mapping and in vivo clonal analysis, to test the hypothesis that Ascl1+ neocortical progenitors are
oligodendrocyte-fate restricted; 2) Under the second aim, in vivo clonal analyses in combination with dose-
controlled loss-of-function approaches will determine whether precise levels of Shh signaling control the ratio
of different subtypes of oligodendrocyte-lineage cells. The proposed research is significant because it is
expected to provide a better fundamental understanding of the molecular mechanisms underlying
oligodendrocyte specification, and it is the first step toward new advances...

## Key facts

- **NIH application ID:** 10088485
- **Project number:** 5R01NS109239-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Santos Joe Franco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $329,473
- **Award type:** 5
- **Project period:** 2020-02-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10088485

## Citation

> US National Institutes of Health, RePORTER application 10088485, Mechanisms of Oligodendrocyte Fate Specification in the Developing Neocortex (5R01NS109239-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10088485. Licensed CC0.

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