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.

Keywords: CEMIP; PNS injury; differentiation; myelin; neuregulin.