KIAA1199: A novel regulator of MEK/ERK‐induced Schwann cell dedifferentiation

Abstract The molecular mechanisms that regulate Schwann cell (SC) plasticity and the role of the Nrg1/ErbB‐induced MEK1/ERK1/2 signalling pathway in SC dedifferentiation or in myelination remain unclear. It is currently believed that different levels of MEK1/ERK1/2 activation define the state of SC differentiation. Thus, the identification of new regulators of MEK1/ERK1/2 signalling could help to decipher the context‐specific aspects driving the effects of this pathway on SC plasticity. In this perspective, we have investigated the potential role of KIAA1199, a protein that promotes ErbB and MEK1/ERK1/2 signalling in cancer cells, in SC plasticity. We depleted KIAA1199 in the SC‐derived MSC80 cell line with RNA‐interference‐based strategy and also generated Tamoxifen‐inducible and conditional mouse models in which KIAA1199 is inactivated through homologous recombination, using the Cre‐lox technology. We show that the invalidation of KIAA1199 in SC decreases the expression of cJun and other negative regulators of myelination and elevates Krox20, driving them towards a pro‐myelinating phenotype. We further show that in dedifferentiation conditions, SC invalidated for KIAA1199 exhibit lower myelin clearance as well as increased myelination capacity. Finally, the Nrg1‐induced activation of the MEK/ERK/1/2 pathway is severely reduced when KIAA1199 is absent, indicating that KIAA1199 promotes Nrg1‐dependent MEK1 and ERK1/2 activation in SCs. In conclusion, this work identifies KIAA1199 as a novel regulator of MEK/ERK‐induced SC dedifferentiation and contributes to a better understanding of the molecular control of SC dedifferentiation.