KIAA1199: a novel regulator of MEK/ERK-induced Schwann cell dedifferentiation

[en] 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.

Research center :

Giga-Neurosciences et GIGA Molecular Biology of Diseases

Disciplines :

Anatomy (cytology, histology, embryology...) & physiology
Biochemistry, biophysics & molecular biology

Author, co-author :

Boerboom, Angelique; Université de Liège - ULiège > Département des Sciences biomédicales et précliniques

Reusch, Céline ; Université de Liège > GIGA-Research

Pieltain, Alexandra ; Université de Liège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques

Chariot, Alain ; Université de Liège > Département de pharmacie > Chimie médicale

Franzen, Rachelle ; Université de Liège > Département des sciences biomédicales et précliniques > Neuro-anatomie

Language :

English

Title :

KIAA1199: a novel regulator of MEK/ERK-induced Schwann cell dedifferentiation

Publication date :

October 2017

Journal title :

Glia

ISSN :

0894-1491

eISSN :

1098-1136

Publisher :

Wiley Liss, Inc., New York, United States - New York

Volume :

Issue :

Pages :

1682-1696

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]

Available on ORBi :

since 27 July 2017

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