Summary: Researchers have uncovered a key biological mechanism that promotes myelin repair and regeneration by studying the interaction between the Daam2 protein and the kinase CK2α. Myelin, the insulating sheath that enables fast, accurate nerve signaling, is essential for healthy brain function; when it is damaged, it contributes to serious neurological conditions.
This research highlights the Wingless (Wnt) signaling pathway as a central regulator of myelin regeneration and identifies how Daam2 restrains myelination. The findings point to new opportunities for therapeutic strategies in disorders marked by myelin loss.
Key Facts:
- Daam2 and the kinase CK2α are critical regulators of myelin repair and oligodendrocyte development.
- Loss or damage of the myelin sheath contributes to neurological disorders including multiple sclerosis, cerebral palsy, and outcomes after brain injury.
- CK2α phosphorylates Daam2, a modification that promotes oligodendrocyte differentiation and suggests a potential route for enhancing myelin regeneration.
Source: Texas Children’s Hospital
Study overview
A team led by Dr. Hyun Kyoung Lee, associate professor at Baylor College of Medicine and investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, described a previously unrecognized mechanism that controls myelin formation and repair. Their work identifies how Daam2, a Dishevelled-associated activator of morphogenesis, and the Ser/Thr kinase CK2α cooperate to regulate Wnt signaling during oligodendrocyte (OL) development and after injury.
Oligodendrocytes produce myelin, the multilayered membrane that insulates axons and ensures rapid neurotransmission. Damage to this sheath is central to many neurological diseases in adults, such as multiple sclerosis, and in infants, such as cerebral palsy, and is commonly observed after brain injuries. Restoring myelin is therefore a major goal in neurology.
The Wnt signaling pathway is a major regulator of OL development and myelin regeneration. Elevated Wnt activity in white matter, as seen after certain injuries and in some disease states, can impede myelin production by keeping oligodendrocytes in a stalled, undifferentiated state. Earlier work from Dr. Lee’s group showed that Daam2 prevents oligodendrocyte differentiation and myelin repair, but the molecular mechanism remained unclear.
To clarify how Daam2 controls myelination, the researchers first mapped regulatory sites on the Daam2 protein and identified two adjacent residues—Ser704 and Thr705—that undergo phosphorylation. Phosphorylation is a common post-translational modification that alters protein activity and interactions.
Comparing gene expression profiles between wild-type animals and animals engineered to carry a constitutively phosphorylated form of Daam2, the team observed consistent changes in pathways that govern lipid and cholesterol metabolism as well as alterations in multiple signaling cascades including Wnt. Because Daam2 is known to modulate canonical Wnt signaling, the investigators examined how these gene expression changes relate to Wnt pathway activity.
A detailed, stage-specific analysis showed that phosphorylation of Daam2 changes how Wnt/β-catenin signaling operates across oligodendrocyte development. Notably, Daam2 phosphorylation has distinct effects depending on the developmental stage: it accelerates early differentiation of progenitor cells into immature oligodendrocytes, but later it slows their maturation and myelin production. This stage-dependent regulation clarifies seemingly contradictory roles of Wnt signaling during OL lineage progression.
To identify the kinase responsible for phosphorylating Daam2, the team performed motif analysis and biochemical screens, which highlighted CK2. They confirmed that the catalytic subunit CK2α binds to and phosphorylates Daam2 in cultured oligodendrocytes. Both Daam2 and CK2α show increased expression that parallels oligodendrocyte lineage progression, and experimental manipulation in vitro and in vivo supports a model in which CK2α promotes OL differentiation through Daam2 phosphorylation.
The researchers also tested the functional importance of this mechanism in injury models. In a neonatal hypoxia model—a form of brain injury relevant to cerebral palsy—CK2α-mediated phosphorylation of Daam2 contributed to better developmental and behavioral recovery. In adult models of white matter injury, the same modification facilitated remyelination, indicating potential therapeutic relevance across ages and injury types.
Overall, these results identify a novel regulatory node in the Wnt pathway: CK2α-dependent phosphorylation of Daam2 alters Wnt complex stability and signaling output, producing stage-specific effects on oligodendrocyte differentiation and myelin formation. By illuminating this mechanism, the study opens new directions for developing therapies aimed at repairing myelin in disorders that currently lack effective treatments.
Dr. Lee emphasized the translational potential: targeting this pathway could one day support strategies to restore myelin and improve outcomes in diseases and injuries marked by white matter damage.
The study’s first author, Chih-Yen Wang, is now an assistant professor at National Cheng Kung University. Other contributors include Zhongyuan Zuo, Juyeon Jo, Kyoung In Kim, Christine Madamba, Qi Ye, Sung Yun Jung, and Hugo J. Bellen. The authors are affiliated with Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital.
Funding: This research was supported by grants from NIH/NINDS, the National Multiple Sclerosis Society, the Cynthia and Anthony G. Petrello Endowment, the Mark A. Wallace Endowment, and the Eunice Kennedy Shriver National Institute of Child Health & Human Development for BCM IDDRC cores. Additional support for mouse line generation and single-cell RNA sequencing was provided by institutional cores.
About this neuroscience research news
Author: Rajalaxmi Natarajan
Source: Texas Children’s Hospital
Contact: Rajalaxmi Natarajan – Texas Children’s Hospital
Image: The image is credited to Neuroscience News
Abstract
Daam2 phosphorylation by CK2α negatively regulates Wnt activity during white matter development and injury
Wnt signaling is essential for both developmental and regenerative myelination in the central nervous system. The pathway comprises multiple regulatory layers, and how those layers coordinate oligodendrocyte development has been unclear. The study demonstrates that CK2α phosphorylates Daam2, inhibiting Daam2’s function and reducing Wnt activity during oligodendrocyte development. Daam2 phosphorylation has stage-specific effects—enhancing early differentiation but slowing later maturation and myelination. In models of white matter injury, CK2α-mediated phosphorylation of Daam2 supports developmental and behavioral recovery after neonatal hypoxia and aids myelin repair in adult demyelination. Together, these findings define a protein phosphorylation–dependent regulatory node in Wnt signaling that governs oligodendrocyte development and reveals a new mechanism to promote myelin restoration.