# Deciphering the mechanisms of glia development and white matter injury > **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $501,343 ## Abstract SUMMARY AND ABSTRACT Development of myelin, the lipid sheath formed by fully differentiated oligodendrocytes (OLs), is essential for CNS function and plays a variety of roles in supporting neuronal health and activity. Abnormalities in the myelin sheath and subsequent neuronal impairment are responsible for the neurologic consequences of white matter injury (WMI). Upregulation of canonical Wnt activity has been reported in patients with WMI, and aberrant activation of Wnt signaling is an adverse event for remyelination. However, manipulating Wnt regulators using genetic models has produced inconsistent outcomes, possibly because these Wnt components interact with other pathways, affect transcriptional partners at different stages of the OL lineage, and/or have Wnt-independent functions. Therefore, a critical knowledge gap is the need to understand the temporal dynamics and molecular mechanisms underlying Wnt signaling at different stages of OL development and after WMI. Previously, we discovered that the formin protein Daam2 (Dishevelled associated activator of morphogenesis 2), a component of the Wnt receptor complex, suppresses OL differentiation and yet is also required for myelination during development. These observations raise an intriguing question: how does Daam2 play seemingly opposite roles during OL lineage development? Answering this question is essential for devising novel therapeutic strategies for white matter disorders. To begin to answer this question, we performed multi-omics profiling and discovered that phosphorylated Daam2 attenuates Wnt signaling in the OL lineage and promotes OL differentiation while mitigating myelination during development. We also identified CK2α (Casein kinase II-α) as the kinase that phosphorylates Daam2 and triggers its ubiquitin- mediated proteolysis by the ubiquitin E3 ligase Trim28 (Tripartite motif-containing 28). Moreover, in WMI mouse models, both CK2α and Daam2 phosphorylation were found to promote tissue repair. Based on these compelling preliminary findings, we hypothesize that CK2-induced Daam2 phosphorylation and subsequent degradation is a key post-translational mechanism that attenuates Wnt signaling and promotes remyelination after injury. To address this hypothesis, we will first determine how Daam2 phosphorylation by CK2α contributes to Wnt signaling during OL development and after WMI (Aim 1). Second, we will determine the mechanisms of Daam2 phosphorylation-induced degradation during OL development and after WMI (Aim 2). Upon completion, these studies will decipher the crucial role of Daam2 and its post-translational regulation in the stage-specific OL lineage. Our findings will deliver clinically applicable insights into regulatory pathways, potentially filling a critical unmet need for patients with WMI. ## Key facts - **NIH application ID:** 10796595 - **Project number:** 2R01NS110859-06 - **Recipient organization:** BAYLOR COLLEGE OF MEDICINE - **Principal Investigator:** Hyun Kyoung Lee - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $501,343 - **Award type:** 2 - **Project period:** 2019-02-01 → 2029-01-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10796595 ## Citation > US National Institutes of Health, RePORTER application 10796595, Deciphering the mechanisms of glia development and white matter injury (2R01NS110859-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10796595. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*