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In addition to its well\u2010defined roles in energy homeostasis, FGF21 has been shown to promote remyelination after injury in the central nervous system. In the current study, we sought to examine the potential roles of FGF21 in the peripheral nervous system (PNS) myelination. In the PNS myelin development, <jats:italic>Fgf21<\/jats:italic> expression was reversely correlated with myelin gene expression. In cultured primary Schwann cells (SCs), the application of recombinant FGF21 greatly attenuates myelination\u2010associated gene expression, including <jats:italic>Oct6<\/jats:italic>, <jats:italic>Krox20<\/jats:italic>, <jats:italic>Mbp<\/jats:italic>, <jats:italic>Mpz<\/jats:italic>, and <jats:italic>Pmp22<\/jats:italic>. Accordingly, the injection of FGF21 into neonatal rats markedly mitigates the myelination in sciatic nerves. On the contrary, the infusion of the anti\u2010FGF21 antibody accelerates the myelination. Mechanistically, both extracellular signal\u2010regulated kinase (ERK) and p38 mitogen\u2010activated protein kinase (MAPK) were stimulated by FGF21 in SCs and sciatic nerves. Following experiments including pharmaceutical intervention and gene manipulation revealed that the p38 MAPK\/c\u2010Jun axis, rather than ERK, is targeted by FGF21 for mediating its repression on myelination in SCs. Taken together, our data provide a new aspect of FGF21 by acting as a negative regulator for the myelin development process in the PNS via activation of p38 MAPK\/c\u2010Jun.<\/jats:p>","DOI":"10.1002\/jcp.29942","type":"journal-article","created":{"date-parts":[[2020,7,13]],"date-time":"2020-07-13T10:24:19Z","timestamp":1594635859000},"page":"1345-1361","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["FGF21 impedes peripheral myelin development by stimulating p38 MAPK\/c\u2010Jun axis"],"prefix":"10.1002","volume":"236","author":[{"given":"Yunzhong","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory for Neuroregeneration of Jiangsu Province and Ministry of Education, Co\u2010Innovation Center of Neuroregenetation, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair Nantong University  Nantong Jiangsu China"},{"name":"School of Medicine Nantong University  Nantong 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