# How do non-myelinating glia ensheath axons?

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $336,875

## Abstract

Project summary
Glial ensheathment of axons is a conserved feature of nervous systems that is essential for proper nervous system
function. Impairment or loss of axonal wrapping underlies many debilitating conditions including multiple sclerosis,
leukodystrophies, peripheral neuropathies, and CMT diseases. Despite many years of work our understanding of the
molecular pathways that control glial development, glial-axon communication, and ensheathment of long axons, including
myelination, is far from complete. Our understanding of non-myelinating forms of axon ensheathment is particularly
sparse, despite the fact that the majority of peripheral axons (~70%) in humans are unmyelinated and encased by Remak
Schwann cells. To address this gap in our understanding we propose to use the genetically tractable model Drosophila to
characterize novel molecular mechanisms that promote glial ensheathment of axons and to study the functional roles of
non-myelinating ensheathment in axon health and function in vivo. In Drosophila, specialized glia called wrapping glia
(WG) ensheath peripheral axons in a manner closely resembling vertebrate Remak SCs. Recent studies (including our
own preliminary data) have found that many genes that control the formation of vertebrate myelin also control axon
ensheathment by WG in the fly, supporting strong molecular conservation between these forms of ensheathment. We have
taken advantage of the fly to conduct a large-scale RNAi screen for novel regulators of ensheathment, and have identified
a number of exciting new genes required for glial ensheathment of axons. One candidate to emerge from the screen,
discoidin domain receptor (Ddr), encodes an evolutionarily conserved receptor tyrosine kinase activated by collagens.
We show that loss of Ddr in WG results in profound defects in axonal ensheathment: although WG can grow
longitudinally along the nerve they fail to insert processes between bundled axons to sort and ensheath them. Intriguingly,
murine Ddr1 is highly expressed in oligodendrocytes and detailed expression profiling reveals that mDdr1 expression
increases at the onset of wrapping during development and with the initiation of remyelination after injury, but functional
roles for mDdr in ensheathment or myelination has not been investigated. Our preliminary work has also identified the
Type XV/XVIII collagen homolog Multiplexin as required for axon ensheathment, possibly by acting as a ligand for Ddr.
In Aim 1 we will characterize the role of Ddr in promoting axonal ensheathment, determine its autonomy of action, and
perform a structure function analysis to define key aspects of Ddr signaling in vivo. In Aim 2 we will investigate the role
of Mp in driving ensheathment and directly test our model that Mp acts in an autocrine fashion to activate the Ddr
receptor on WG. Finally, in Aim 3 we will take advantage of the many genes identified in the screen that have mild to
strong ensheathment defects to probe the function of...

## Key facts

- **NIH application ID:** 10137334
- **Project number:** 5R01NS112215-03
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Marc R Freeman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $336,875
- **Award type:** 5
- **Project period:** 2019-06-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137334

## Citation

> US National Institutes of Health, RePORTER application 10137334, How do non-myelinating glia ensheath axons? (5R01NS112215-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10137334. Licensed CC0.

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