Laurence Richard

Adenosine deaminase acting on RNA 1 (ADAR1) is the principal enzyme for the adenosine-to-inosine RNA editing that prevents the aberrant activation of cytosolic nucleic acid sensors by endogenous double stranded RNAs and the activation of interferon-stimulated genes. In mice, the conditional neural crest deletion of Adar1 reduces the survival of melanocytes and alters the differentiation of Schwann cells that fail to myelinate nerve fibers in the peripheral nervous system. These myelination defects are partially rescued upon the concomitant removal of the Mda5 antiviral dsRNA sensor in vitro, suggesting implication of the Mda5/Mavs pathway and downstream effectors in the genesis of Adar1 mutant phenotypes. By analyzing RNA-Seq data from the sciatic nerves of mouse pups after conditional neural crest deletion of Adar1 (Adar1cKO), we here identified the transcription factors deregulated in Adar1cKO mutants compared to the controls. Through Adar1;Mavs and Adar1cKO;Egr1 double-mutant mouse rescue analyses, we then highlighted that the aberrant activation of the Mavs adapter protein and overexpression of the early growth response 1 (EGR1) transcription factor contribute to the Adar1 deletion associated defects in Schwann cell development in vivo. In silico and in vitro gene regulation studies additionally suggested that EGR1 might mediate this inhibitory effect through the aberrant regulation of EGR2-regulated myelin genes. We thus demonstrate the role of the Mda5/Mavs pathway, but also that of the Schwann cell transcription factors in Adar1-associated peripheral myelination defects.

Introduction: Peripheral neuropathy is a common symptom throughout the population, with numerous possible etiologies. The diagnosis of peripheral neuropathies (and their causes) is mainly based on clinical, electrophysiological, biological, and imaging features. Areas covered: This paper reviews the main causes of neuropathy and discusses the usefulness of nerve biopsy (NB) in such cases. Expert commentary: In most cases, NB is not mandatory in the diagnostic work-up of a peripheral neuropathy. However, NB is clearly an indication in cases of vasculitis. It is also valuable in peripheral neuropathies with severe and rapid worsening (without clear cause) in order to uncover a pathological hallmark (amyloid deposits). Although NB is considered an invasive method, it may be useful in the management of peripheral neuropathy, especially to guide treatment in certain cases. In summary, although NB is not a systematic procedure, it is a useful tool that should be discussed on a case-by-case basis within the clinical context.

Astrocytes encompass a heterogeneous cell population. Using sedimentation field-flow fractionation (SdFFF) method, different, almost pure, astrocyte subpopulations were isolated. Cells were collected from cortex of newborn rats and sorted by SdFFF to obtain different fractions, which were subjected to protein analysis and characterized by immunocytofluorescence. The behavior of the cells was analyzed in vitro , under culture conditions used for neural stem cells. These culture conditions were also applied to cells derived from an adult cortical tissue after traumatic brain injury (TBI). Finally, the astrocytic neural stem-like cells were transplanted in damaged sciatic nerve. Protein analysis indicated a high expression of glial fibrillary acidic protein (GFAP) and vimentin in fraction F3-derived cells. These cells formed neurospheres when cultured with epidermal growth factor and large colonies in a collagen-containing semi-solid matrix. Neurospheres expressed GFAP and nestin and were able in addition to generate neurons expressing MAP2 and oligodendrocytes expressing Olig2. When transplanted in a damaged nerve, cells of F3-derived neurospheres colonized the damaged area. Finally, after TBI in adult rats, cells able to form neurospheres containing a subpopulation of astrocytes expressing vimentin were obtained. Using the SdFFF method, an astrocyte subpopulation presenting stem cell properties was isolated from a newborn rat cortex and from an injured adult rat cortex. The specific activation of this astrocyte subpopulation may provide a potential therapeutic approach to restore lost neuronal function in injured or diseased brain.