Biology subjects

Meschkat, M.

Publications and source records attributed to Meschkat, M..

6 recordsLinked to original sources

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↗

bioRxiv2024

Vascular development of fetal and postnatal neocortex of the pig, the European wild boar Sus scrofa.

The development of the brains vascular system is a predominantly prenatal process in mammalian species and required for neurogenesis and further brain development. Our recent work on fetal pig has revealed that many neurodevelopmental processes start well before birth and proceed rapidly reaching near-mature status already around birth. Here, we analyzed the development of neocortical vasculature from embryonic day (E) 45 onwards (gestation in pig lasts 114 days) using qualitative and quantitative image analyses and protein blots. In all cortical layers, vessel volume from total brain volume at E100 resembled that of a postnatal day (P) 30 piglet. Endothelial cells expressed the tight junction protein claudin-5 from E45 onwards. GFAP+ and AQP4+ astrocytes, PDGFR{beta}+ pericytes and -SMA+ smooth muscle cells are detectable near vessels at E60 suggesting an early assembly of blood-brain barrier components. The vascular system in the visual cortex is advanced before birth with an almost mature pattern at E100. Findings were confirmed by blots which showed a steady increase of expression of tight junction and angiogenesis-related proteins (claudin-5, occludin, VE-cadherin, PECAM-1/CD31) from E65 onwards until P90. The expression profile was similar in visual and somatosensory cortex. Together, we report a rapid maturation of the vascular system in pig cortex. Regarding activity-dependent aspects, the data suggest that angiogenesis might be influenced by spontaneous rather than sensory-evoked activity. Author contributionConceptualization and methodology: ES and PW; investigation and analysis: ES, KC; provided resources: CB, CB, MM, DU; visualization: ES, MM, DU; writing--original draft: ES, PW; writing--review and editing: ES, GM, PW; supervision and project administration: PW. All authors approved the manuscript. Summary statementVascular impairment is associated with neurodegenerative disorders. As a groundwork for future studies, we quantitatively analyzed development of cortical vasculature in the emerging translational model, the pig. ETHICAL APPROVALAll applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures were in accordance with the ethical standards or practice of the institution at which the studies were conducted.

developmental biology↗

bioRxiv2023

Intrinsic microtubule destabilization of multiciliated choroid plexus epithelial cells during postnatal lifetime

Choroid plexus (ChP) epithelium is composed of specialized multiciliated cells. By using multiple microscopic techniques, biochemical approaches in various mutant mice and longitudinal analysis from mouse embryogenesis to aging, we show that ChP cilia are built on a gradient of events which are spatio-temporally regulated. We uncover that ChP cilia develop prenatally since early tissue morphogenesis, and proceeds as a multi-step process characterized by basal body multiplication and axoneme formation directly at the apical cellular compartment. Our data also show that choroid plexus cilia contain both primary and motile features. Remarkably, we demonstrate that ChP cilia undergo axoneme resorption, starting from early youth, through a tubulin destabilization process, which is primarily controlled by polyglutamylation levels and could be mitigated by the removal of the microtubule-severing enzyme spastin. Notably, we demonstrate that this phenotype is preserved in human samples.

developmental biology↗

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↗

bioRxiv2020

White matter integrity requires continuous myelin synthesis at the inner tongue

Myelin, the electrically insulating axonal sheath, is composed of lipids and proteins with exceptionally long lifetime. This raises the question how myelin function is affected by myelin turnover. We have studied the integrity of myelinated tracts after experimentally preventing the formation of new myelin in the CNS of adult mice, using an inducible Mbp null allele. Oligodendrocytes survived recombination, continued expressing myelin genes, but failed to maintain compacted myelin sheaths. Using 3D electron microscopy and mass spectrometry imaging we visualized myelin-like membranes that failed to incorporate adaxonally, most prominently at juxta-paranodes. Myelinoid body formation indicated degradation of existing myelin at the abaxonal side and at the inner tongue of the sheath. Compacted myelin thinning and shortening of internodes, with about 50% myelin lost after 20 weeks (=5 months), ultimately led to axonal pathology and neurological disease. These data reveal that functional axon-myelin units require the continuous incorporation of new myelin membranes.

neuroscience↗

bioRxiv2019

A role of oligodendrocytes in information processing independent of conduction velocity

Myelinating oligodendrocytes enable fast impulse propagation along axons as revealed through studies of homogeneously myelinated white matter tracts. However, gray matter myelination patterns are different, with sparsely myelinated sections leaving large portions of the axons naked. The consequences of this patchy myelination for oligodendrocyte function are not understood but suggest other roles in information processing beyond the regulation of axonal conduction velocity. Here, we analyzed the contribution of myelin to auditory information processing using paradigms that are good predictors of speech understanding in humans. We compared mice with different degrees of dysmyelination using acute cortical multiunit recordings in combination with behavioral readouts. We identified complex alterations of neuronal responses that reflect fatigue and temporal acuity deficits. Partially discriminable but overall similar deficits were observed in mice with oligodendrocytes that can myelinate but cannot fully support axons metabolically. Thus, myelination contributes to sustained stimulus perception in temporally complex paradigms, revealing a role of oligodendrocytes in the CNS beyond the increase of axonal conduction velocity.

neuroscience↗