Artikel
Glial Neuregulin-1 regulates Schwann cell pathology in Charcot-Marie-Tooth disease-1A
Suche in Medline nach
Autoren
Veröffentlicht: | 14. September 2016 |
---|
Gliederung
Text
Introduction: Charcot-Marie-Tooth disease 1A (CMT1A) is the most common inherited neuropathy, caused by a duplication of the gene encoding for the peripheral myelin protein of 22kDA (PMP22). Histologically, peripheral nerves of patients affected by CMT1A demonstrate a characteristic Schwann cell pathology, including hypermyelination of small caliber axons, segmental demyelination as well as supernumerary Schwann cells and onion bulb formations. However, the nature of these disease hallmarks remains largely unknown.
Objectives: We here aimed at understanding the molecular mechanisms that induce this characteristic, histological Schwann cell response in CMT1A disease. In a first approach, we therefore searched for genes expressed by Schwann cells that are known to be involved in cell differentiation and myelination.
Materials and Methods: We combined mouse genetics, light and electron microscopic analyses as well as transcriptional and biochemical methods.
Results: We here demonstrate that the soluble growth factor Neuregulin-1 (Nrg-1) type I is induced in Schwann cells of CMT1A disease. Of note, we previously showed that Nrg-1 type I, expressed by SC, promotes nerve repair after acute nerve injury. With the help of different mutant and transgenic mice, we identified Schwann cell derived Nrg-1 as a major regulator of Schwann cell pathology in a mouse model for CMT1A disease. In detail, CMT1A mice lacking Schwann cell derived Nrg-1 demonstrate a strong amelioration of the characteristic disease hallmarks including dysmyelination and onion bulb formations, along with an improvement of the clinical phenotype. In contrast, transgenic mice overexpressing Nrg-1 type I in Schwann cells mimic a demyelinating peripheral neuropathy on histological level.
Conclusion: We here suggest a model in which Schwann cells in peripheral nerve diseases mount a common regeneration program which is beneficial after acute nerve injury, but turns into a detrimental persistent response in chronic peripheral nerve disease such as CMT1A.