# Deciphering the Daam2-VHL signaling axis in oligodendrocyte development and white matter injury

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $346,719

## Abstract

SUMMARY and ABSTRACT
Glia comprise approximately 60% of the cellular constituency of central nervous system (CNS), playing diverse
roles in the functioning CNS and a host of neurological disorders. Development of glial cell lineages proceeds
along a tightly regulated program that involves patterning, generation of diverse cells, differentiation, and
myelination. This cascade of developmental events is particularly vulnerable to neonatal hypoxic brain injury,
which leads to profound loss of myelinating oligodendrocytes (OLs), extensive white matter damage,
culminating in neuronal dysfunction. Despite the robust regenerative capacity of OLs, the underlying
mechanisms mediating hypomyelination and the subsequent defects in neural circuits after hypoxic injury
remain poorly defined. Moreover, myelination continues throughout early adulthood, which also renders the
CNS susceptible to insults causing late-onset neurodegeneration. Therefore, the overarching goal of this
application is to define new genes and pathways that drive OL maturation during development and repair, and
pinpoint potential targetable pathways for white matter disorders. Previously, we identified Daam2
(Disheveled associated activator of morphogenesis 2) as a pivotal regulator of OL myelination and repair, and
recently discovered that Daam2 governs OL differentiation through ubiquitination of the hypoxia regulator
VHL (von Hippel-Lindau). Moreover, we discovered that Daam2 is regulated by two E3 ligases, Nedd4 (Neural
precursor cell expressed developmentally down-regulated protein 4) and Trim9 (Tripartite Motif Containing
9), which in turn govern VHL ubiquitination and OL differentiation. These observations raise two key
questions that we will pursue in this proposal: 1) how does Daam2 modulate VHL-HIF signaling in OLs? and 2)
how is the ubiquitin-mediated Daam2 degradation controlled in OLs? By understanding the in-depth
mechanisms by which Daam2 operates, we will establish Daam2 inhibition as a clinically significant and
actionable strategy for the treatment of white matter injury. To answer these key questions, we will first define
the reciprocal relationship between Daam2 and VHL during OL development and white matter injury (Aim 1).
These studies will define the Daam2-VHL axis as a pivotal regulator of OL development, while revealing novel
connections between Wnt signaling and hypoxic pathway during OL myelination. Next, we will determine
Daam2 proteasomal degradation pathways in OLs (Aim 2). Upon completion, these studies will define how
Daam2 is regulated by target E3 ligases, and identify Nedd4 and Trim9 as novel regulators of OL myelination.
A mechanistic understanding of Daam2-VHL axis function in oligodendrocyte repair after injury will shed light
on cellular vulnerability to white matter injury and ultimately point to new venues for therapeutic development
to stimulate OL remyelination.

## Key facts

- **NIH application ID:** 9858448
- **Project number:** 5R01NS110859-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Hyun Kyoung Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $346,719
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858448

## Citation

> US National Institutes of Health, RePORTER application 9858448, Deciphering the Daam2-VHL signaling axis in oligodendrocyte development and white matter injury (5R01NS110859-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9858448. Licensed CC0.

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