# The role of mTOR signaling in oligodendrocyte differentiation and CNS myelination

> **NIH NIH R37** · UNIVERSITY OF COLORADO DENVER · 2020 · $752,441

## Abstract

To understand oligodendrocyte differentiation and myelin formation in the CNS, it is essential to define how
intracellular signaling pathways regulate the cytoplasmic and nuclear events that drive myelination. A number
of signaling pathways have been implicated in driving CNS myelination. The collaborative project between the
Macklin and Wood laboratories was initiated to define the function specifically of mTOR signaling in
oligodendrocyte and myelin biology. Over the past several years, our laboratories have contributed significant
findings on the function of mTOR and its associated complexes through this successful collaboration. The
current application addresses a fundamental gap in understanding the mechanisms by which mTOR regulates
oligodendrocyte differentiation and myelination through regulating specific downstream targets. Our earlier
studies demonstrated that oligodendrocyte loss of mTOR or raptor, the mTORC1-associated protein, results in
deficits in oligodendrocyte differentiation and initiation of myelination in the spinal cord. Moreover, we found
that these mice have reduced myelin thickness that was sustained in the adult spinal cord. A significant
strength of the studies is that we have also begun to define distinct mTOR-dependent and –independent
pathways that regulate developmental myelination in the brain versus spinal cord. The goal of the current
studies is to address the fundamental questions of 1) what are the mTOR-dependent mechanisms that
regulate the conversion of oligodendrocyte progenitors to differentiating oligodendrocytes through regulating
transcriptional machinery, 2) how does mTOR regulate specific cytoskeletal changes necessary for initiation of
myelination and myelin wrapping, and 3) how does the crosstalk between mTORC2 and integrin-linked kinase
(ILK) pathways regulate myelination in the corpus callosum? We will address these questions in both rodent
and zebrafish models by testing the following hypotheses: 1) mTOR promotes oligodendrocyte differentiation
by suppressing bone morphogenetic pathway (BMP) signaling and down-regulating transcriptional inhibitors, 2)
mTOR promotes initiation of myelination through regulating specific cytoskeletal targets during both process
extension and axon wrapping, and 3) rictor regulates myelination in the corpus callosum through promoting
Akt473 phosphorylation in coordination with both mTOR and ILK.

## Key facts

- **NIH application ID:** 9976589
- **Project number:** 5R37NS082203-09
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** WENDY B MACKLIN
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $752,441
- **Award type:** 5
- **Project period:** 2012-09-30 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976589

## Citation

> US National Institutes of Health, RePORTER application 9976589, The role of mTOR signaling in oligodendrocyte differentiation and CNS myelination (5R37NS082203-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9976589. Licensed CC0.

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