Biology subjects

Nave, K.-A.

Publications and source records attributed to Nave, K.-A..

At least 19 recordsLinked to original sources

bioRxiv2026

A single-nucleus regulatory atlas links transposable elements to adult hippocampal neurogenesis

Adult hippocampal neurogenesis can be enhanced or even triggered by extrinsic stimuli, but the lineage-specific regulatory changes that accompany a stimulated neurogenic response remain undefined. We used recombinant human erythropoietin (rhEPO), a defined influencing factor that enriches newly formed pyramidal neurons by ~2 fold in this paradigm, to profile ~35,000 nuclei by single-nucleus ATAC sequencing (snATAC-seq) from rhEPO- and placebo-treated adult mouse hippocampi and to integrate them with matched single-nucleus RNA sequencing (snRNA-seq) of ~120,000 nuclei. Thirty-five accessibility-defined clusters resolved 11 major lineages. Of 39,404 differentially accessible regions (DARs), more than half arose in pyramidal neurons, whereas dentate gyrus granule neurons and interneurons showed predominantly reduced accessibility; within the pyramidal lineage, remodelling was predominant in newly-formed rather than mature neurons. About 20% of hippocampal candidate cis-regulatory elements (cCREs) overlapped transposable elements (TEs) at baseline, rising to about 50% among regions that gained accessibility upon stimulation, and multiple families were significantly bound above the expected threshold by neurogenic transcription factors, whereby the many neighbouring genes have established roles for neuronal differentiation and synapse formation. These data define TE-derived sequences as candidate components of stimulus-responsive neurogenic regulatory networks and provide a cell-type-specific chromatin resource for the adult hippocampus at single-nucleus resolution.

neuroscience↗

bioRxiv2026

Mutant SOD1 expressed by oligodendrocytes aggregates in myelinic nanochannels and accelerates disease progression in familial ALS mice

Amyotrophic lateral sclerosis (ALS) is a highly debilitating and fatal disease characterized by the progressive loss of motor neurons. Reduced oligodendroglial support has been implicated in ALS progression but remains mechanistically unexplained. Here, using a mutant superoxide dismutase 1 (SOD1-G37R) mouse model of familial ALS, Cre-mediated excision of the mutant SOD1 gene within the oligodendrocyte lineage prior to myelin compaction is shown to slow disease onset, improve motor performance, and prolong survival. In contrast, silencing mutant SOD1 expression within oligodendrocytes after myelin compaction failed to ameliorate disease phenotype. Electron microscopy is used to identify aggregation of mutant SOD1 within paranodal loops and the inner periaxonal tongue of myelinic nanochannels, narrow cytosolic compartments for the diffusion of metabolites and motor-driven transport processes. In a second mouse model (SOD1-G93A) of familial, SOD1 mutant-mediated ALS, we show that induction of excessive myelin compaction and myelinic channel collapse (by depletion of CNP from myelin) accelerates disease and diminishes survival. Our data support loss of myelinic channel integrity as a contributor to familial ALS disease initiation and progression, findings likely relevant to neurodegenerative disease involving other aggregation prone proteins that are expressed in myelinating oligodendrocytes. Significance StatementOligodendrocytes have been implicated in the progression of amyotrophic lateral sclerosis (ALS) but the underlying mechanisms have remained obscure. Here we show in genetic mouse models that the familial ALS causing isoform of a ubiquitously expressed mutant enzyme (SOD1) aggregates in cytosolic channels within myelin that are responsible for delivery of transporters and nutrients necessary to support the axonal compartment. ALS disease progression was accelerated in mice when myelinic channels were collapsed by deleting CNP, a structural protein necessary for myelinic channel maintenance. Disruption of transport through myelinic channels by aggregation of mutant SOD1 may perturb oligodendrocyte support of motor axons and contribute to disease in this form of ALS.

neuroscience↗

bioRxiv2026

Fatty acid binding protein-8 (FABP8/PMP2) reveals molecular heterogeneity of myelin sheaths in the human CNS

Myelin is classically viewed as a uniform axon-insulating membrane, yet its molecular composition may differ between species and even within one species. Fatty acid binding protein-8 (FABP8/PMP2) was previously identified in CNS myelin of humans but not mice. Here we show that FABP8/PMP2 is a defining feature of CNS myelin in humans and old-world-monkeys, but absent from CNS myelin in other mammals, indicating evolutionary neofunctionalization of this lipid-binding protein in the primate lineage. In the human CNS, FABP8/PMP2 marks a subset of myelin sheaths that preferentially ensheath large-diameter axons, revealing sheath-to-sheath molecular heterogeneity correlated with axonal geometry. Chromatin is accessible at the PMP2/Pmp2 gene locus in oligodendrocytes of humans but not mice. Human oligodendrocytes intrinsically express FABP8/PMP2 when transplanted into mouse brains, demonstrating species-specific competence independent of environmental cues. Humanized transgenic mice expressing FABP8/PMP2 in oligodendrocytes form morphologically normal but developmentally transiently thicker myelin sheaths, and show elevated cholesterol content in purified myelin. Because FABP8/PMP2 binds cholesterol, we propose that its emergence in primate CNS myelin contributes to the cholesterol enrichment of human myelin. Thus, CNS myelin protein composition is evolvable and modular, with relevance for myelin lipids and morphology, and previously unrecognized complexity in neuron-glia co-adaptation. Main points- Fatty acid binding protein 8 (FABP8/PMP2) is present in CNS myelin of humans and old-world monkeys - PMP2 defines sheath-to-sheath heterogeneity in the human CNS - PMP2-immunopositive myelin ensheaths large-diameter axons - Human oligodendrocytes intrinsically express PMP2 upon transplantation into mice - Humanized PMP2-transgenic mice show thicker myelin and altered myelin lipid composition

neuroscience↗

bioRxiv2026

Red fluorescent labeling of myelin by membrane-targeted tdTomato in transgenic mouse lines

Myelin is a highly complex membranous structure wrapped around axons by oligodendrocytes or Schwann cells in the central and peripheral nervous system, respectively. Fluorescent labeling is widely used to study the structure and dynamics of myelin. Combining structural with functional imaging requires labeling of myelin with red fluorescence, as many functional sensors, including Ca2+ indicators and genetically encoded metabolite sensors, fluoresce in the green spectral range. However, in vivo tools enabling red fluorescent labeling of myelinating cells and their myelin sheaths remain limited. Here, we generated a set of seven transgenic mouse lines expressing a membrane-targeted variant of the red fluorescent protein tdTomato in myelinating oligodendrocytes and Schwann cells throughout the nervous system. The mouse lines provide a variety of expression patterns ranging from wide-spread labeling of myelin to a rather sparse expression, the latter enabling visualization of individual oligodendrocytes and their associated myelin sheaths. In the peripheral nervous system, the pattern of fluorescence in sciatic nerves indicates predominant localization of tdTomato to non-compact myelin compartments including the inner and outer tongues, paranodal loops and Schmidt-Lanterman incisures. In summary, our work provides a set of novel mouse lines with myelin labeled by red fluorescence, which are compatible with diverse imaging modalities in the green spectral range enabling integrated structural and functional imaging. Main PointsO_LITransgenic mouse lines expressing membrane-targeted tdTomato in myelin enable imaging of myelin in the red spectral range C_LIO_LIDistinct expression patterns range from wide-spread labeling to sparse single-cell resolution, supporting diverse imaging applications C_LI

neuroscience↗

bioRxiv2025

Tether-mediated extraction of myelinoid bodies by microglia and astrocytes can maintain myelin integrity

Oligodendrocytes make myelin for the electrical insulation of axons and saltatory impulse conduction. Myelin lipids and proteins undergo a slow turnover, but exactly how the multilamellar and compacted membrane sheaths are remodeled without compromising myelin sheath integrity has remained puzzling, in particular at advanced age when myelin abnormalities increase. Earlier EM studies had suggested myelin membranes are shed and subsequently phagocytosed by microglia. However, the formation of multilamellar myelinoid bodies (MBs), leaving a well-ordered myelin sheath behind, is difficult to reconcile with simple shedding mechanisms. Here, we show by three-dimensional FIB-SEM reconstructions of optic nerves in mice and by two-photon live-imaging of myelinated cortical slices that MBs are initially connected to their parental sheaths by long tethers, which are stretched by trogocytosing microglia and astrocytes. We observe ruptured tethers attached to both MBs and sheaths, suggesting a novel mechanism of tension-driven tether scission. Importantly, the successive fusion of the corresponding innermost myelin membranes in an extended tether can preserve myelin sheath integrity. Thus, the remodeling by tether-mediated MB extraction emerges as a mechanism of physiological maintenance of myelin sheaths in the CNS.

neuroscience↗

bioRxiv2025

Transposable Element-Mediated Epigenomic Remodeling Drives Erythropoietin-Induced Neurogenesis in the Adult Hippocampus

Understanding the molecular mechanisms by which erythropoietin (EPO) acts as neurotrophic factor that enhances hippocampal function and learning is essential to harness its therapeutic potential. Here, we employ single-nucleus ATAC-seq and RNA-seq to map the epigenomic and transcriptional landscapes of adult mouse hippocampus under recombinant human EPO (rhEPO) treatment. We discover significant lineage-specific chromatin remodeling predominantly in newly formed and immature excitatory neurons, highlighting a robust EPO-driven neurogenic response as the first direct evidence that an extrinsic factor can induce adult hippocampal neurogenesis. Notably, many EPO-induced accessible regions overlap ancient transposable elements, particularly ancient LINEs and SINEs, that are bound by key neurogenic transcription factors such as NEUROD1/2, NEUROG2, FOXG1, and ASCL1 and are linked to nearby genes governing neuronal differentiation and synaptic plasticity. Our findings uncover a previously unrecognized transposon-mediated mechanism underlying EPO-induced neurogenesis, highlighting an underappreciated role for TE-derived sequences in this process, and establish a publicly available single-nucleus multiomic atlas as a resource for understanding cell-type-specific gene regulation and neuroplasticity in the adult brain.

neuroscience↗

bioRxiv2025

Adaptor protein complex 2 (AP2) participates in biogenesis and homeostasis of myelin sheaths in the central nervous system

Myelination of CNS axons requires oligodendrocytes to undergo extensive morphological changes by producing large amounts of myelin membrane with defined protein composition and structure. The formation of myelin sheaths thus involves efficient trafficking and sorting of future myelin constituents via vesicles that fuse with prospective myelin membranes by exocytotic mechanisms. However, the functional relevance of other trafficking steps in oligodendocytes for myelin biogenesis is largely unknown. Here, we followed the hypothesis that developmental myelination involves endocytic mechanisms. In this model, Golgi-derived vesicles fuse with the oligodendroglial plasma membrane, from which myelin constituents are retrieved by endocytosis into endosomal/lysosomal organelles before their final integration into the growing sheath. Considering that adaptor protein complex-2 subunit-{micro} (AP2M) facilitates AP2-dependent endocytosis, we recombined the Ap2m-gene in myelin-forming oligodendrocytes, causing both hypomyelination and specific changes in the myelin proteome. Most strikingly, lysosomal membrane proteins accumulate in the abaxonal (outermost) myelin layer, identifying this membrane as an active site for retrieving constituents from myelin sheaths. These data demonstrate that the AP2 complex serves a critical function in developmental myelination in vivo. Unexpectedly, we also observed pathological myelin outfoldings indicative of focal hypermyelination. Consistent with the hypothesis that this phenotype reflects impaired maintenance rather than biogenesis of myelin sheaths, recombination of the Ap2m-gene in oligodendrocytes of adult mice caused late-onset progressive focal hypermyelination. These results indicate that, in addition to astrocytic and microglial phagocytosis, oligodendrocytes cell-autonomously contribute to maintaining the structure of healthy myelin sheaths via AP2-dependent mechanisms.

neuroscience↗

bioRxiv2025

Neuropeptide CRH prevents premature differentiation of OPCs following CNS injury and in early postnatal development

The role of neuropeptides and their receptors in oligodendrocyte progenitor cells (OPCs) has largely been overlooked so far. Here, we describe a new subpopulation of corticotropin-releasing hormone (CRH)-expressing OPCs that aggregate around acute brain injuries and exhibit an elevated capacity to differentiate into myelinating oligodendrocytes (OLs). We found that CRH expression in OPCs is rapidly induced de novo as a transient response within the first 72 hours after injury. As target cells, we identified CRH receptor type 1 (CRHR1)-expressing OPCs which show a decreased differentiation velocity. We demonstrate that CRH/CRHR1 system inactivation increases the speed of OL generation compromising the long-term survival of OLs after acute injury. Furthermore, we prove that a CRH/CRHR1 system deficiency under non-injury conditions leads to increased early postnatal oligodendrogenesis and alterations in adult myelination. Altogether, we show that OPC-derived CRH not only actively influences the injury environment through the interaction with CRHR1-expressing OPCs, but also identify the G-protein coupled receptor CRHR1 as a critical modulator of oligodendrogenesis at early postnatal stages with lasting effects on adult myelination.

neuroscience↗

bioRxiv2024

A myelinic channel system for organelle transport to the glial-axonal junction

Myelin sheaths comprise compacted layers of oligodendroglial membrane wrapped spirally around axons. Each sheath, if imagined unwrapped, has a cytoplasm-filled space at its perimeter, linking it to the oligodendrocyte soma via a short process. By electron microscopy (EM), this space, which we term the myelinic channel system contains microtubules and membranous organelles, but whether these are remnants of development or serve a function is unknown. Performing live imaging of myelinating oligodendrocytes expressing fluorescent reporters, we found that the myelinic channel system serves microtubule-dependent organelle transport. Further, the intra-myelinic movement of peroxisomes was modulated by neuronal electrical activity in these mixed neural cell cultures. Loss of oligodendroglial Kif21b or CNP in vivo led to apparent stasis of myelin organelles and secondary axon pathology. This suggests that oligodendrocytes require motor transport in myelin to maintain axonal integrity.

neuroscience↗

bioRxiv2024

IntelliR: A comprehensive and standardized pipeline for automated profiling of higher cognition in mice

In the rapidly evolving field of rodent behavior research, observer-independent methods facilitate data collection within a social, stress-reduced, and thus more natural environment. A prevalent system in this research area is the IntelliCage, which empowers experimenters to design individual tasks and higher cognitive challenges for mice, driven by their motivation to access reward. The extensive amount and diversity of data provided by the IntelliCage system explains the growing demand for automated analysis among users. Here, we introduce IntelliR, a standardized pipeline for analyzing raw data generated by the IntelliCage software, as well as novel parameters including the cognition index, which enables comparison of performance across various challenges. With IntelliR, we provide the tools to implement and automatically analyze 3 challenges that we designed, encompassing spatial, episodic-like, and working memory with their respective reversal tests. Using results from 3 independent control cohorts of adult female wildtype mice, we demonstrate their ability to comprehend and learn the tasks, thereby improving their proficiency over time. To validate the sensitivity of our approach for detecting cognitive impairment, we used adult female NexCreERT2xRosa26-eGFP-DTA mice after tamoxifen induced diphtheria toxin-mediated ablation of pyramidal neurons in cortex and hippocampus. We observed deterioration in learning capabilities and cognition index across several tests. IntelliR can be readily integrated into and adapted for individual research, thereby improving time management and reproducibility of data analysis. HIGHLIGHTSO_LIIntelliR is a standardized pipeline for analyzing raw data of IntelliCage software. C_LIO_LIDomains include spatial, episodic-like, and working memory with reversals. C_LIO_LIWT mice (3 cohorts) comprehend, learn and improve proficiency over time. C_LIO_LICognition index permits comparison of performance across cognitive domains. C_LIO_LIMice with ablation of pyramidal neurons decline mainly in working memory. C_LI

animal behavior and cognition↗

bioRxiv2023

Oligodendrocytes and neurons contribute to amyloid-β deposition in Alzheimer's disease

In Alzheimers disease (AD), amyloid-{beta} (A{beta}) is thought to be of neuronal origin. However, in single-cell RNAseq datasets from mouse and human, we found transcripts of amyloid precursor protein (APP) and the amyloidogenic-processing machinery equally abundant in oligodendrocytes (OLs). By cell-type-specific deletion of Bace1 in a humanized knock-in AD model, APPNLGF, we demonstrate that almost a third of cortical A{beta} deposited in plaques is derived from OLs. However, excitatory projection neurons must provide a threshold level of A{beta} production for plaque deposition to occur and for oligodendroglial A{beta} to co-aggregate. Indeed, very few plaques are deposited in the absence of neuronally-derived A{beta}, although soluble A{beta} species are readily detected, especially in subcortical white matter. Our data identify OLs as a source of A{beta} in vivo and further underscore a non-linear relationship between cellular A{beta} production and resulting plaque formation. Ultimately, our observations are relevant for therapeutic strategies aimed at disease prevention in AD.

neuroscience↗

bioRxiv2023

Transcriptional networks predating cognition-associated pyramidal lineages are restructured by erythropoietin

Recombinant human erythropoietin (rhEPO) has potent procognitive effects, hematopoiesis-independent, but underlying mechanisms and physiological role of brain-expressed EPO have remained obscure. Here, we provide encyclopedic transcriptional hippocampal profiling of mice treated with rhEPO. Based on [~]108,000 single nuclei, we unmask multiple pyramidal lineages with their comprehensive molecular signatures. By temporal profiling and gene regulatory analysis, we build a developmental trajectory of CA1 pyramidal neurons derived from multiple predecessor lineages and elucidate gene regulatory networks underlying their fate determination. With EPO as tool, we discover novel populations of newly differentiating pyramidal neurons, overpopulating to [~]200% upon rhEPO with upregulation of genes crucial for neurodifferentiation, dendrite growth, synaptogenesis, memory formation, and cognition. Using a Cre-based approach to visually distinguish pre-existing from newly formed pyramidal neurons for patch-clamp recordings, we learn that rhEPO treatment differentially affects excitatory and inhibitory inputs. Our findings provide mechanistic insight into how EPO modulates neuronal functions and networks.

neuroscience↗

bioRxiv2022

Isolated catatonia-like executive dysfunction in micewith forebrain-specific loss of myelin integrity

A key feature of advanced brain aging includes structural defects of intracortical myelin that are associated with secondary neuroinflammation. A similar pathology is seen in specific myelin mutant mice that model advanced brain aging and exhibit a range of behavioral abnormalities. However, the cognitive assessment of these mutants is problematic because myelin-dependent motor-sensory functions are required for quantitative behavioral readouts. To better understand the role of cortical myelin integrity for higher brain functions, we generated mice lacking Plp1, encoding the major integral myelin membrane protein, selectively in ventricular zone stem cells of the mouse forebrain. In contrast to conventional Plp1 null mutants, subtle myelin defects were restricted to the cortex, hippocampus and underlying callosal tracts. Moreover, forebrain-specific Plp1 mutants exhibited no defect of basic motor-sensory performance at any age tested. Surprisingly, several behavioral alterations reported for conventional Plp1 null mice (Gould et al., 2018) were absent and even social interactions appeared normal. However, with novel behavioral paradigms, we determined catatonia-like symptoms and isolated executive dysfunction in both genders. This suggests that loss of myelin integrity has an impact on cortical connectivity and underlies specific defects of executive function. These observations are likewise relevant for human neuropsychiatric conditions and other myelin-related diseases.

neuroscience↗

bioRxiv2022

Potassium regulates axon-oligodendrocyte signaling and metabolic coupling in white matter

The integrity of myelinated axons relies on homeostatic support from oligodendrocytes (OLs), which is essential for brain function. However, the mechanisms by which OLs detect axonal spiking and rapidly control axon-OL metabolic coupling are largely unknown. Here, we combine optic nerve electrophysiology and two-photon imaging to study activity-dependent calcium (Ca2+) dynamics in OLs and metabolite fluxes in myelinated axons. Both high-frequency axonal firing and extracellular potassium (K+) elevations trigger a fast Ca2+ response in OLs that is facilitated by barium-sensitive, inwardly rectifying K+ channels. Using OL-specific Kir4.1 knockout mice (Kir4.1 cKO) we now demonstrate that, in addition to being crucial for K+ clearance, oligodendroglial Kir4.1 regulates axonal energy metabolism and long-term axonal integrity. Before the manifestation of axonal damage, we observed reduced glucose transporter GLUT1 and monocarboxylate transporter MCT1 expression in myelin of young Kir4.1 cKO mice, suggesting early deficits in metabolite supply to axons. Strikingly, we found lower resting lactate levels and activity-induced lactate surges in optic nerve axons of young Kir4.1 cKO mice. Moreover, both axonal glucose uptake and consumption were hampered in the absence of oligodendroglial Kir4.1, uncovering a new role of OLs in regulating axonal glucose metabolism. Our findings reveal a novel model of axon-OL signaling and metabolic coupling in which OLs detect high-frequency axonal activity through K+ signaling, which is critical in adjusting the axon-OL metabolic unit and in preserving long-term axonal health.

neuroscience↗

bioRxiv2022

Axo-vascular coupling mediated by oligodendrocytes

The high energy requirements of the cortical gray matter are met by the precise cooperation of neurons, glia, and vascular cells in a process known as neurovascular coupling (NVC). In contrast, the existence and significance of NVC in white matter (WM) are still debated and basic regulatory mechanisms are unknown. We recently discovered that oligodendrocytes sense the spiking axons activity via NMDA receptors and regulate their cell surface expression of glucose transporter GLUT1 allowing an increase in glycolytic metabolism that enables lactate release to metabolically support the axons. Here, we show for the mouse optic nerve (ON), a model WM tract, that the vascular support is also dynamically controlled. Axonal spiking activity induces small vessel dilations which are sustained for more than 20 minutes upon the ending of electrical stimulation. Pharmacological inhibition shows that the electrically evoked dilation is mediated by the prostaglandin E2 receptor EP4 and can be modulated by the oxygen concentration, as has been shown in the grey matter. Importantly, we found in ONs from conditional mouse mutants that oligodendroglial NMDA receptors are required for this type of neurovascular response, demonstrating a critical role of oligodendrocytes in coupling axonal activity to pericyte function. Reminiscent of NVC in cortical slices, the "axo-vascular" response is slower and may represent a more rudimentary form of neurovascular coupling.

neuroscience↗

bioRxiv2022

Myelin lipids as nervous system energy reserves

Neuronal functions and impulse propagation depend on the continuous supply of glucose1,2. Surprisingly, the mammalian brain has no obvious energy stores, except for astroglial glycogen granules3. Oligodendrocytes make myelin for rapid axonal impulse conduction4 and also support axons metabolically with lactate5-7. Here, we show that myelin itself, a lipid-rich membrane compartment, becomes a local energy reserve when glucose is lacking. In the mouse optic nerve, a model white matter tract, oligodendrocytes survive glucose deprivation far better than astrocytes, by utilizing myelin lipids which requires oxygen and fatty acid beta-oxidation. Importantly, fatty acid oxidation also contributes to axonal ATP and basic conductivity. This metabolic support by fatty acids is an oligodendrocyte function, involving mitochondria and myelin-associated peroxisomes, as shown with mice lacking Mfp2. To study reduced glucose availability in vivo without physically starving mice, we deleted the Slc2a1 gene from mature oligodendrocytes. This caused a significant decline of the glucose transporter GLUT1 from the myelin compartment leading to myelin sheath thinning. We suggest a model in which myelin turnover under low glucose conditions can transiently buffer axonal energy metabolism. This model may explain the gradual loss of myelin in a range of neurodegenerative diseases8 with underlying hypometabolism9.

neuroscience↗

bioRxiv2022

Conservation and divergence of myelin proteome and oligodendrocyte transcriptome profiles between humans and mice

Human myelin disorders are commonly studied in mouse models. Since both clades evolutionarily diverged approximately 85 million years ago, it is critical to know to what extent the myelin protein composition has remained similar. Here we use quantitative proteomics to analyze myelin purified from human white matter and find that the relative abundance of the structural myelin proteins PLP, MBP, CNP and SEPTIN8 correlates well with that in C57Bl/6N- mice. Conversely, multiple other proteins were identified exclusively or predominantly in human or mouse myelin. This is exemplified by peripheral myelin protein-2 (PMP2), which was specific to human CNS myelin, while tetraspanin-2 (TSPAN2) and connexin-29 (CX29/GJC3) were confined to mouse myelin. Assessing published scRNA-seq-datasets, human and mouse oligodendrocytes display well-correlating transcriptome profiles but divergent expression of distinct genes including Pmp2, Tspan2 and Gjc3. Species-dependent diversity of oligodendroglial mRNA-expression and myelin protein composition can be informative when translating from mouse models to humans.

neuroscience↗

bioRxiv2021

Progressive axonopathy when oligodendrocytes lack the myelin protein CMTM5

Oligodendrocytes facilitate rapid impulse propagation along the axons they myelinate and support their long-term integrity. However, the functional relevance of many myelin proteins has remained unknown. Here we find that expression of the tetraspan-transmembrane protein CMTM5 (Chemokine-like factor-like MARVEL-transmembrane domain containing protein 5) is highly enriched in oligodendrocytes and CNS myelin. Genetic disruption of the Cmtm5-gene in oligodendrocytes of mice does not impair the development or ultrastructure of CNS myelin. However, oligodendroglial Cmtm5-deficiency causes an early-onset progressive axonopathy, which we also observe in global and in tamoxifen-induced oligodendroglial Cmtm5-mutants. Presence of the Wlds mutation ameliorates the axonopathy, implying a Wallerian degeneration-like pathomechanism. These results indicate that CMTM5 is involved in the function of oligodendrocytes to maintain axonal integrity rather than myelin biogenesis.

neuroscience↗