Open AccessmiR-322 stabilizes MEK1 expression to inhibit RAF/MEK/ERK pathway activation in cartilage
Author(s) -
Björn Bluhm,
Harald W.A. Ehlen,
Tatjana Holzer,
Veronika S. Georgieva,
Juliane Heilig,
Lena Pitzler,
Julia Etich,
Toman Borteçen,
Christian Frie,
Kristina Probst,
Anja Niehoff,
Daniele Belluoccio,
Jocelyn van den Bergen
Publication year - 2017
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.148429
Subject(s) - mapk/erk pathway , microbiology and biotechnology , cartilage , biology , chondrocyte , downregulation and upregulation , microrna , signal transduction , phosphorylation , transcriptome , gene expression , anatomy , gene , biochemistry
Cartilage originates from mesenchymal cell condensations that differentiate into chondrocytes of transient growth plate cartilage or permanent cartilage of the articular joint surface and trachea. MicroRNAs fine-tune the activation of entire signaling networks and thereby modulate complex cellular responses, but so far only limited data are available on miRNAs that regulate cartilage development. Here we characterize a miRNA which promotes the biosynthesis of a key component in the RAF/MEK/ERK pathway in cartilage. Specifically, by transcriptome profiling we identified miR-322 to be upregulated during chondrocyte differentiation. Among the various miR-322 target genes in the RAF/MEK/ERK pathway only Mek1 was identified as a regulated target in chondrocytes. Surprisingly, an increased concentration of miR-322 stabilizes Mek1-mRNA to rise protein levels and dampen ERK1/2 phosphorylation, while cartilage-specific inactivation in mice linked the loss of miR-322 to decreased MEK1 levels and increased RAF/MEK/ERK pathway activation. Such mice died perinatally due to tracheal growth restriction and respiratory failure. Hence, a single miRNA can stimulate the production of an inhibitory component of a central signaling pathway to impair cartilage development.