# How Does Actin Disassembly Drive Myelin Wrapping?

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $397,945

## Abstract

PROJECT SUMMARY/ABSTRACT
Myelin—the electrical insulator around neuronal axons—is essential in vertebrates for rapid nerve signaling,
and its loss in diseases like multiple sclerosis and following injury causes severe disability in patients. In the
central nervous system, oligodendrocytes build myelin by first extending their membrane processes to
ensheath axons, then wrapping spirally around the axon while compacting their membranes to become
electrically insulating. In chronic multiple sclerosis lesions, oligodendrocytes ensheath axons but fail to wrap,
suggesting that wrapping is a rate-limiting step for remyelination. To ultimately understand why remyelination
fails in multiple sclerosis, we first aim to understand the mechanism by which myelin wraps normally. It was
long hypothesized that the assembly of actin filaments provides the force required to drive wrapping, like the
lamellipodium of a motile cell or a neuronal growth cone. However, we and others recently discovered that the
dramatic disassembly of the oligodendrocyte actin cytoskeleton is required for wrapping. This finding was
completely unexpected and suggests two models for wrapping. Cycles of actin disassembly and reassembly
could be required to “ratchet” the oligodendrocyte membrane forward. In contrast, based on our preliminary
data, we propose that actin disassembly acts as a “trigger” to initiate actin-independent wrapping and that the
major role of actin disassembly is to allow myelin to compact. To test these models, we are using a suite of
innovative approaches including first-in-class genetic tools we created to experimentally induce actin
disassembly (DeActs) or block actin disassembly (StablActs) in oligodendrocytes during wrapping in vivo,
advanced microscopy techniques to resolve myelin in vivo, and live cell imaging of oligodendrocytes in culture.
Our preliminary data demonstrate: (1) actin filaments disassemble in oligodendrocytes prior to wrapping, (2)
experimentally inducing actin disassembly specifically in oligodendrocytes in vivo increases myelin wrapping,
and (3) experimentally blocking actin disassembly impairs myelin membrane compaction in a culture model of
myelination. These data support the “trigger” model of myelin wrapping, laying the foundation for future
translational studies to test whether this actin disassembly-based mechanism is recapitulated or perturbed
during remyelination. By defining the role of actin disassembly in myelin wrapping and compaction, this project
will open up new research directions towards understanding myelin formation, plasticity, and disease in the
central nervous system.

## Key facts

- **NIH application ID:** 10692704
- **Project number:** 5R01NS119823-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** John B Zuchero
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $397,945
- **Award type:** 5
- **Project period:** 2020-09-30 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10692704

## Citation

> US National Institutes of Health, RePORTER application 10692704, How Does Actin Disassembly Drive Myelin Wrapping? (5R01NS119823-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10692704. Licensed CC0.

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