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. 2017 Oct 1;144(19):3562-3577.
doi: 10.1242/dev.148429. Epub 2017 Aug 29.

miR-322 stabilizes MEK1 expression to inhibit RAF/MEK/ERK pathway activation in cartilage

Björn Bluhm  1   2 , Harald W A Ehlen  1   2 , Tatjana Holzer  1   2 , Veronika S Georgieva  1   2 , Juliane Heilig  3   4 , Lena Pitzler  1   2 , Julia Etich  1   2 , Toman Bortecen  1   2 , Christian Frie  1   2 , Kristina Probst  1   2 , Anja Niehoff  3   4 , Daniele Belluoccio  5   6 , Jocelyn Van den Bergen  5   7 , Bent Brachvogel  8   2   4
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miR-322 stabilizes MEK1 expression to inhibit RAF/MEK/ERK pathway activation in cartilage

Björn Bluhm et al. Development. .

Abstract

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 that 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 raise protein levels and dampen ERK1/2 phosphorylation, while cartilage-specific inactivation of miR322 in mice linked the loss of miR-322 to decreased MEK1 levels and to 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.

Keywords: CRISPR; Cartilage; MAPK; MEK; Stabilization; miR-322.

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