Biology subjects

Doan, R. A.

Publications and source records attributed to Doan, R. A..

4 recordsLinked to original sources

bioRxiv2025

Developmental axon diameter growth of central nervous system axons does not depend on ensheathment or myelination by oligodendrocytes

Myelination facilitates the rapid conduction of action potentials along axons. In the central nervous system (CNS), myelinated axons vary over 100-fold in diameter, with conduction speed scaling linearly with increasing diameter. Axon diameter and myelination are closely interlinked, with axon diameter exerting a strong influence on myelination. Conversely, myelinating Schwann cells in the peripheral nervous system can both positively and negatively affect axon diameter. However, whether axon diameter is regulated by CNS oligodendrocytes is less clear. Here, we investigated CNS axon diameter growth in the absence of myelin using mouse (Mbpshi/shi and Myrf conditional knockout) and zebrafish (olig2 morpholino) models. We find that neither the ensheathment of axons, nor the formation of compact myelin are required for CNS axons to achieve appropriate and diverse diameters. This indicates that developmental CNS axon diameter growth is independent of myelination, and shows that myelinating cells of CNS and PNS differentially influence axonal morphology.

neuroscience↗

bioRxiv2024

TMEM63A, associated with hypomyelinating leukodystrophies, is an evolutionarily conserved regulator of myelination

Infantile hypomyelinating leukodystrophy 19 (HLD19) is a rare genetic disorder where patients exhibit reduced myelin in central nervous system (CNS) white matter tracts and present with varied neurological symptoms. The causative gene TMEM63A encodes a mechanosensitive ion channel whose role in myelination has not been explored. Our study shows that TMEM63A is a major regulator of OL-driven myelination in the CNS. In mouse and zebrafish, Tmem63a inactivation led to early deficits in myelination, recapitulating the HLD19 phenotype. OL-specific conditional mouse knockouts of Tmem63a exhibited transient reductions in myelin, indicating that TMEM63A regulates myelination cell-autonomously. We show that TMEM63A is present at plasma membrane and on lysosomes and modulates myelin/myelin-associated protein production. Intriguingly, HLD19-associated TMEM63A variants from patients blocked trafficking to cell membrane. Together, our results reveal an ancient role for TMEM63A in fundamental aspects of myelination in vivo and highlight two exciting new models for the development of treatments for devastating hypomyelinating leukodystrophies.

neuroscience↗

bioRxiv2024

FBXW7 regulates MYRF levels to control myelin capacity and homeostasis in the adult CNS

Myelin, along with the oligodendrocytes (OLs) that produce it, is essential for proper central nervous system (CNS) function in vertebrates. Although the accurate targeting of myelin to axons and its maintenance are critical for CNS performance, the molecular pathways that regulate these processes remain poorly understood. Through a combination of zebrafish genetics, mouse models, and primary OL cultures, we found FBXW7, a recognition subunit of an E3 ubiquitin ligase complex, is a regulator of adult myelination in the CNS. Loss of Fbxw7 in myelinating OLs resulted in increased myelin sheath lengths with no change in myelin thickness. As the animals aged, they developed progressive abnormalities including myelin outfolds, disrupted paranodal organization, and ectopic ensheathment of neuronal cell bodies with myelin. Through biochemical studies we found that FBXW7 directly binds and degrades the N-terminal of Myelin Regulatory Factor (N-MYRF), to control the balance between oligodendrocyte myelin growth and homeostasis.

neuroscience↗

bioRxiv2023

Dock1 acts cell-autonomously in Schwann cells to regulate the development, maintenance, and repair of peripheral myelin

Schwann cells, the myelinating glia of the peripheral nervous system (PNS), are critical for myelin development, maintenance, and repair. Rac1 is a known regulator of radial sorting, a key step in developmental myelination, and we previously showed in zebrafish that loss of Dock1, a Rac1-specific guanine nucleotide exchange factor, results in delayed peripheral myelination in development. We demonstrate here that Dock1 is necessary for myelin maintenance and remyelination after injury in adult zebrafish. Furthermore, it performs an evolutionary conserved role in mice, acting cell-autonomously in Schwann cells to regulate peripheral myelin development, maintenance, and repair. Additionally, manipulating Rac1 levels in larval zebrafish reveals that dock1 mutants are sensitized to inhibition of Rac1, suggesting an interaction between the two proteins during PNS development. We propose that the interplay between Dock1 and Rac1 signaling in Schwann cells is required to establish, maintain, and facilitate repair and remyelination within the peripheral nervous system.

neuroscience↗