Schwann cells are axo-protective after injury irrespective of myelination status in mouse Schwann cell-neuron cocultures.

Myelinating Schwann cell (SC)-dorsal root ganglion (DRG) neuron cocultures are an important technique for understanding cell-cell signalling and interactions during peripheral nervous system (PNS) myelination, injury, and regeneration. Although methods using rat SCs and neurons or mouse DRG explants are commonplace, there are no established protocols for compartmentalised myelinating cocultures with dissociated mouse cells. There consequently is a need for a coculture protocol that allows separate genetic manipulation of mouse SCs or neurons, or use of cells from different transgenic animals to complement in vivo mouse experiments.

SARM1 detection in myelinating glia: / is dispensable for PNS and CNS myelination in zebrafish and mice.

Since SARM1 mutations have been identified in human neurological disease, SARM1 inhibition has become an attractive therapeutic strategy to preserve axons in a variety of disorders of the peripheral (PNS) and central nervous system (CNS). While SARM1 has been extensively studied in neurons, it remains unknown whether SARM1 is present and functional in myelinating glia? This is an important question to address. Firstly, to identify whether SARM1 dysfunction in other cell types in the nervous system may contribute to neuropathology in SARM1 dependent diseases? Secondly, to ascertain whether therapies altering SARM1 function may have unintended deleterious impacts on PNS or CNS myelination? Surprisingly, we find that oligodendrocytes express mRNA in the zebrafish spinal cord and that SARM1 protein is readily detectable in rodent oligodendrocytes and .

A genetic compensatory mechanism regulated by and modulates the expression of distinct class IIa to ensure peripheral nerve myelination and repair.

The class IIa histone deacetylases (HDACs) have pivotal roles in the development of different tissues. Of this family, Schwann cells express , , and but not . Here, we show that a transcription factor regulated genetic compensatory mechanism within this family of proteins, blocks negative regulators of myelination ensuring peripheral nerve developmental myelination and remyelination after injury.

Neurotoxin-mediated potent activation of the axon degeneration regulator SARM1.

Axon loss underlies symptom onset and progression in many neurodegenerative disorders. Axon degeneration in injury and disease is promoted by activation of the NAD-consuming enzyme SARM1. Here, we report a novel activator of SARM1, a metabolite of the pesticide and neurotoxin vacor.

Lessons from Injury: How Nerve Injury Studies Reveal Basic Biological Mechanisms and Therapeutic Opportunities for Peripheral Nerve Diseases.

Since Waller and Cajal in the nineteenth and early twentieth centuries, laboratory traumatic peripheral nerve injury studies have provided great insight into cellular and molecular mechanisms governing axon degeneration and the responses of Schwann cells, the major glial cell type of peripheral nerves. It is now evident that pathways underlying injury-induced axon degeneration and the Schwann cell injury-specific state, the repair Schwann cell, are relevant to many inherited and acquired disorders of peripheral nerves. This review provides a timely update on the molecular understanding of axon degeneration and formation of the repair Schwann cell.

Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study.

Background: A new syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has emerged as a rare side-effect of vaccination against COVID-19. Cerebral venous thrombosis is the most common manifestation of this syndrome but, to our knowledge, has not previously been described in detail. We aimed to document the features of post-vaccination cerebral venous thrombosis with and without VITT and to assess whether VITT is associated with poorer outcomes.

Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun.

After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during chronic denervation that results from slow axon growth. This impairs axonal regeneration and causes significant clinical problems.

DNA methylation in Schwann cells and in oligodendrocytes.

DNA methylation is one of many epigenetic marks, which directly modifies base residues, usually cytosines, in a multiple-step cycle. It has been linked to the regulation of gene expression and alternative splicing in several cell types, including during cell lineage specification and differentiation processes. DNA methylation changes have also been observed during aging, and aberrant methylation patterns have been reported in several neurological diseases.

Repair Schwann cell update: Adaptive reprogramming, EMT, and stemness in regenerating nerves.

Schwann cells respond to nerve injury by cellular reprogramming that generates cells specialized for promoting regeneration and repair. These repair cells clear redundant myelin, attract macrophages, support survival of damaged neurons, encourage axonal growth, and guide axons back to their targets. There are interesting parallels between this response and that found in other tissues.

Changes in the Coding and Non-coding Transcriptome and DNA Methylome that Define the Schwann Cell Repair Phenotype after Nerve Injury.

Repair Schwann cells play a critical role in orchestrating nerve repair after injury, but the cellular and molecular processes that generate them are poorly understood. Here, we perform a combined whole-genome, coding and non-coding RNA and CpG methylation study following nerve injury. We show that genes involved in the epithelial-mesenchymal transition are enriched in repair cells, and we identify several long non-coding RNAs in Schwann cells.

The Role of Cell Plasticity in Tissue Repair: Adaptive Cellular Reprogramming.

It is becoming clear that a radical change of cell identity of differentiated cells in vivo, triggered by injury or other adversity, provides an essential route to recovery for many different mammalian tissues. This process, which we term adaptive cellular reprogramming, promotes regeneration in one of two ways: by providing a transient class of repair cells or by directly replacing cells lost during tissue damage. Controlling adaptive changes in cell fate in vivo in order to promote the body's own cell therapy, particularly by pharmacology rather than genetics, is likely to become an increasingly active area of future work.

Longevity and Patau syndrome: what determines survival?

The authors report of an 8-year-old girl with non-mosaic Patau syndrome. The median life expectancy of Patau syndrome is 7-10 days, and 90% die in the first year of life. Survival is often attributed to mosaicism and the severity of associated malformations.

c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration.

The radical response of peripheral nerves to injury (Wallerian degeneration) is the cornerstone of nerve repair. We show that activation of the transcription factor c-Jun in Schwann cells is a global regulator of Wallerian degeneration. c-Jun governs major aspects of the injury response, determines the expression of trophic factors, adhesion molecules, the formation of regeneration tracks and myelin clearance and controls the distinctive regenerative potential of peripheral nerves.

Mouse schwann cells need both NRG1 and cyclic AMP to myelinate.

Genetically modified mice have been a major source of information about the molecular control of Schwann-cell myelin formation, and the role of β-neuregulin 1 (NRG1) in this process in vivo. In vitro, on the other hand, Schwann cells from rats have been used in most analyses of the signaling pathways involved in myelination. To correlate more effectively in vivo and in vitro data, we used purified cultures of mouse Schwann cells in addition to rat Schwann cells to examine two important myelin-related signals, cyclic adenosine monophosphate (cAMP), and NRG1 and to determine whether they interact to control myelin differentiation.

Novel signals controlling embryonic Schwann cell development, myelination and dedifferentiation.

Immature Schwann cells found in perinatal rodent nerves are generated from Schwann cell precursors (SCPs) that originate from the neural crest. Immature Schwann cells generate the myelinating and non-myelinating Schwann cells of adult nerves. When axons degenerate following injury, Schwann cells demyelinate, proliferate and dedifferentiate to assume a molecular phenotype similar to that of immature cells, a process essential for successful nerve regeneration.

c-Jun is a negative regulator of myelination.

Schwann cell myelination depends on Krox-20/Egr2 and other promyelin transcription factors that are activated by axonal signals and control the generation of myelin-forming cells. Myelin-forming cells remain remarkably plastic and can revert to the immature phenotype, a process which is seen in injured nerves and demyelinating neuropathies. We report that c-Jun is an important regulator of this plasticity.

A double point mutation in the DNA-binding region of Egr2 switches its function from inhibition to induction of proliferation: A potential contribution to the development of congenital hypomyelinating neuropathy.

Mutations in the DNA-binding domain of EGR2 are associated with severe autosomal dominant forms of peripheral neuropathy. In this study, we show that one such Egr2 mutant (S382R, D383Y), when expressed in Schwann cells in vitro, is not transcriptionally inactive but retains residual wild-type Egr2 functions, including inhibition of transforming growth factor-beta-induced Schwann cell death and an ability to induce the cytoskeletal protein periaxin. More importantly, this mutant Egr2 has aberrant effects in Schwann cells, enhancing DNA synthesis both in the presence and absence of the putative axonal mitogen, beta-neuregulin 1.