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Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy.

ABSTRACT: Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 (NRG1) type III regulate Schwann cell fate and myelination. Here we ask if modulating NRG1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we improved the myelination defects by early overexpression of NRG1 type III. Surprisingly, the improvement was independent from the upregulation of Egr2 or essential myelin genes. Rather, we observed the activation of MAPK/ERK and other myelin genes such as peripheral myelin protein 2 and oligodendrocyte myelin glycoprotein. We also confirmed that the permanent activation of MAPK/ERK in Schwann cells has detrimental effects on myelination. Our findings demonstrate that the modulation of axon-to-glial NRG1 type III signaling has beneficial effects and improves myelination defects during development in a model of CHN.

SUBMITTER: Belin S

PROVIDER: S-EPMC6452193 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy.

Belin Sophie S Ornaghi Francesca F Shackleford Ghjuvan'Ghjacumu G Wang Jie J Scapin Cristina C Lopez-Anido Camila C Silvestri Nicholas N Robertson Neil N Williamson Courtney C Ishii Akihiro A Taveggia Carla C Svaren John J Bansal Rashmi R Schwab Markus H MH Nave Klaus K Fratta Pietro P D'Antonio Maurizio M Poitelon Yannick Y Feltri M Laura ML Wrabetz Lawrence L

Human molecular genetics 20190401 8

Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 (NRG1) type III regulate Schwann cell fate and myelination. Here we ask if modulating NRG1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we improved the myelination defects by early overexp ...[more]

PMID: 30535360

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Project description:BackgroundG-CSF has been shown to increase neuronal survival, which may positively influence the spinal cord microenvironment during the course of muscular dystrophies.Methodology/principal findingsMale MDX mice that were six weeks of age received a left sciatic nerve transection and were treated with intraperitoneal injections of 200 µg/kg/day of G-CSF 7 days before and 7 days after the transection. The axotomy was performed after the cycles of muscular degeneration/regeneration, consistent with previous descriptions of this model of muscular dystrophy. C57BL/10 mice were used as control subjects. Seven days after the surgery, the animals were sacrificed and their lumbar spinal cords were processed for immunohistochemistry (anti-MHC I, anti-Synaptophysin, anti-GFAP and anti-IBA-1) and transmission electron microscopy. MHC I expression increased in both strains of mice after the axotomy. Nevertheless, the MDX mice displayed a significantly smaller MHC I upregulation than the control mice. Regarding GFAP expression, the MDX mice showed a stronger astrogliosis compared with the C57BL/10 mice across all groups. Both groups that were treated with G-CSF demonstrated preservation of synaptophysin expression compared with the untreated and placebo groups. The quantitative analysis of the ultrastructural level showed a preservation of the synaptic covering for the both groups that were treated with G-CSF and the axotomized groups showed a smaller loss of synaptic contact in relation to the treated groups after the lesion.Conclusions/significanceThe reduction of active inputs to the alpha-motoneurons and increased astrogliosis in the axotomized and control groups may be associated with the cycles of muscle degeneration/regeneration that occur postnatally. The G-CSF treated group showed a preservation of the spinal cord microenvironment after the lesion. Moreover, the increase of MHC I expression in the MDX mice that were treated with G-CSF may indicate that this drug performs an active role in regenerative potential after lesions.

Project description:Previously, we demonstrated i) that ergocalciferol (vitamin D2) increases axon diameter and potentiates nerve regeneration in a rat model of transected peripheral nerve and ii) that cholecalciferol (vitamin D3) improves breathing and hyper-reflexia in a rat model of paraplegia. However, before bringing this molecule to the clinic, it was of prime importance i) to assess which form - ergocalciferol versus cholecalciferol - and which dose were the most efficient and ii) to identify the molecular pathways activated by this pleiotropic molecule. The rat left peroneal nerve was cut out on a length of 10 mm and autografted in an inverted position. Animals were treated with either cholecalciferol or ergocalciferol, at the dose of 100 or 500 IU/kg/day, or excipient (Vehicle), and compared to unlesioned rats (Control). Functional recovery of hindlimb was measured weekly, during 12 weeks, using the peroneal functional index. Ventilatory, motor and sensitive responses of the regenerated axons were recorded and histological analysis was performed. In parallel, to identify the genes regulated by vitamin D in dorsal root ganglia and/or Schwann cells, we performed an in vitro transcriptome study. We observed that cholecalciferol is more efficient than ergocalciferol and, when delivered at a high dose (500 IU/kg/day), cholecalciferol induces a significant locomotor and electrophysiological recovery. We also demonstrated that cholecalciferol increases i) the number of preserved or newly formed axons in the proximal end, ii) the mean axon diameter in the distal end, and iii) neurite myelination in both distal and proximal ends. Finally, we found a modified expression of several genes involved in axogenesis and myelination, after 24 hours of vitamin supplementation. Our study is the first to demonstrate that vitamin D acts on myelination via the activation of several myelin-associated genes. It paves the way for future randomised controlled clinical trials for peripheral nerve or spinal cord repair.

Dataset Information

Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy.

Publications

Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy.

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