The Etv1/Er81 transcription factor coordinates myelination-related genes to regulate Schwann cell differentiation and myelination

Abstract

Background: Axonal myelination is critical for the functioning of vertebrate nervous system. Myelin sheath malformation or degeneration can cause a variety of neurological diseases. Our previous study identified multiple potential myelination-related transcriptional factors (TFs), including expressed sequence tag (ETS) variant transcription factor 1 (Etv1)/Er81, via gene microarray analysis of Schwann cells (SCs) at various myelination stages. Etv1 is known to be involved in the regulation of neuronal specialization, muscle spindle differentiation, and sensorimotor connectivity. However, to our knowledge, to date, there are no relevant studies that Etv1 regulates SC myelination. Methods: To investigate the roles of Etv1 in SC re-myelination, an in vivo mouse myelination model was used, in which the sciatic nerve is crushed. Etv1 in nerves was knocked down via in situ injection of cholesterol-modified Etv1-small interfering (si)RNA. The expression of myelin-associated glycoprotein (MAG) was evaluated by Western blotting (WB) and immunohistochemistry (IHC). Myelination was assessed by transmission electron microscopy (TEM). The effects of Etv1 on SC proliferation, migration, and differentiation were assessed in vitro using the EdU cell proliferation kit, a culture-insert scratch assay, a SC aggregate sphere migration assay on the axons of dorsal root ganglions (DRGs), and a SC differentiation model. Chromatin immunoprecipitation (ChIP) united with quantitative real-time PCR (qPCR), known as ChIP-qPCR, and luciferase activity reporter assays were performed to explore the possible mechanisms by which Etv1 controls SC differentiation and myelination. Results: The results demonstrated that Etv1 promoted myelination by facilitating SC proliferation, migration, and differentiation. Etv1 expression in SCs was upregulated during re-myelination, and knocking down Etv1 expression dramatically abrogated SC re-myelination in the crushed sciatic nerves. Moreover, silencing of Etv1 by siRNA in SCs in vitro inhibited its migration, proliferation, and differentiation. The results of ChIP-qPCR and luciferase reporter assay showed that Etv1 may regulate SC differentiation and myelination by binding to the promoters of myelination-related genes, such as MAG and Runx2, to initiate their transcription. Conclusions: Taken together, these findings demonstrated a previously unknown role of Etv1 in SC differentiation and myelination, providing a candidate molecular target for clinical interventions in demyelinating diseases.

Adipose stem cells in tissue regeneration and repair: From bench to bedside

“…Glial cells, also known as Schwann cells (SCs), play a key role in the regeneration of peripheral nerves [ 108 ]. In the repair process of peripheral nerve injury, SCs can down-regulate the expression of myelin-related genes and up-regulate the expression of growth-related genes, and further synthesize exogenous neurotrophic factors (NTFs), cell adhesion molecules NCAM and L1, and myelin-associated glycoprotein (MAG) to promote axonal regeneration and promote the myelination of regenerated axons [ [109] , [110] , [111] , [112] ]. However, it is difficult to obtain and culture SCs [ 113 ], so it is difficult to apply SCs in clinical practice.…”

Trilobatin attenuates cerebral ischaemia/reperfusion‐induced blood–brain barrier dysfunction by targeting matrix metalloproteinase 9: The legend of a food additive

“…The measurements of the BBB were made using Image Pro Plus 6.0 software as follows: Calculation of the number of myelin sheath layers in a uniform scope. Myelin sheath g-ratio was calculated as the ratio of inner diameter to total fibres of a single myelin sheath (Askar et al, 2022). Pericyte coverage was calculated as the ratio of circumference of cerebral capillary lumen covered by a pericyte and vascular lumen circumference.…”

Activation of P2X7R inhibits proliferation and promotes the migration and differentiation of Schwann cells

“…During the myelination process, Schwann cells undergo proliferation, migration, and differentiation to form the myelin sheath. As the Schwann cells differentiate, they reduce their division activity, establish a 1:1 relationship with axons, and upregulate the expression of myelin proteins such as MAG and P0 [23,24].…”