Biology subjects

Marshall-Phelps, K.

Publications and source records attributed to Marshall-Phelps, K..

3 recordsLinked to original sources

bioRxiv2026

Live-imaging of endogenous neurofascins reveals glial adhesion shapes developing nodes of Ranvier

The organisation of myelinated axons into specialised domains is essential for saltatory conduction and depends on the polarised distribution of neuronal and glial cell-adhesion molecules, including neurofascins. However, how these domains assemble and refine in vivo remains unclear, as longitudinal imaging of endogenous proteins within intact nervous systems remains challenging. Here, we generated knock-in zebrafish in which endogenous neuronal and glial neurofascins are fused to fluorescent proteins, which enabled live-imaging without perturbing node assembly or introducing overexpression artefacts. Using these reporters, we visualised neuronal and glial neurofascin dynamics, and the formation of nodes of Ranvier and paranodes in vivo. We find that nascent nodes progressively compact in developing peripheral nerves, and that this process depends on glial neurofascin. Our novel toolkit for imaging endogenous neurofascins reveals a glia-dependent mechanism that shapes the developmental refinement of nodal architecture after their initial assembly. Our findings imply that glia-driven modulation of paranodes can be a mechanism for nervous systems to regulate circuit function.

neuroscience↗

bioRxiv2025

Mislocalisation of TDP-43 to the cytoplasm of either neurons or oligodendrocytes causes axonopathy and dysmyelination

Neurons with large, myelinated axons are vulnerable to degeneration across the amyotrophic lateral sclerosis (ALS) frontotemporal dementia (FTD) disease spectrum. The defining molecular pathology of this spectrum is mislocalisation of the RNA binding protein TDP-43 from the nucleus to the cytoplasm. Even though cytoplasmic TDP-43 is prevalent in neurons and oligodendrocytes, how these molecular pathologies contribute to neurodegeneration remains unclear. Here we developed humanised zebrafish in which we restricted TDP-43 to the cytoplasm of either neurons or oligodendrocytes. Cytoplasmic TDP-43 restricted to neurons led to a severe axonopathy, with extreme distal axonal swelling and reduced myelination. Axonopathy was mirrored by cell type specific loss of TDP-43 function from neurons, pointing to loss of function, rather than a toxic gain of function of mislocalised TDP-43, as driving this phenotype. Preventing oligodendrocyte differentiation and myelination when TDP-43 was mislocalised in neurons exacerbated axonopathy, indicating that oligodendrocytes limit neurodegeneration. Indeed, when TDP-43 was mislocalised to the cytoplasm of oligodendrocytes this also led to axonopathy and reduced myelination, pointing to complex contributions of neurons and oligodendrocytes to neurodegeneration.

neuroscience↗

bioRxiv2025

Internalization of exogenous myelin by oligodendroglia promotes lineage progression

Oligodendrocytes, traditionally recognized for their role in central nervous system myelination, have emerged during the last decades as key participants maintaining brain homoeostasis in response to metabolic demands and stress. In addition, injury to myelin prompts a regenerative response that leads to the formation of new myelin sheaths. However, the signals regulating effective remyelination by oligodendrocytes are still not completely understood. Here, we report that oligodendrocytes can internalize exogenous myelin both in vitro and in vivo, which leads to an increase in their proliferation and differentiation when their functions are not compromised. RNA sequencing reveals that myelin debris alters oligodendrocyte transcriptional profile, suppressing immune-related pathways and de novo cholesterol and fatty acid biosynthesis, while inducing lipid droplet formation to store and process internalized myelin particles. As a result, progression of the oligodendroglial lineage is enhanced in primary cell cultures, as shown by increased viability, proliferation and differentiation. Oligodendrocytes also acquire a more differentiated phenotype, with larger cell areas, a more complex morphology and myelination of synthetic nanofibers. Stereotaxic injection of fluorescent myelin into mouse cortex shows internalization by microglia and, to a lesser extent, by oligodendroglia. Notably, in the zebrafish model, ventricular injections of myelin also increase the number of ventral oligodendrocytes in the spinal cord, further supporting that myelin can promote lineage progression. These findings challenge the classical view that myelin debris intrinsically inhibits oligodendrocyte proliferation, suggesting instead that oligodendrocytes can use myelin to support self-renewal and maturation, acting as a trophic factor in the absence of pathological cues. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/665370v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@b15463org.highwire.dtl.DTLVardef@1b7090org.highwire.dtl.DTLVardef@17b148forg.highwire.dtl.DTLVardef@182d7d1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗