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

Author:

Bluhm Björn12,Ehlen Harald W. A.12,Holzer Tatjana12,Georgieva Veronika S.12,Heilig Juliane34,Pitzler Lena12ORCID,Etich Julia12,Bortecen Toman12,Frie Christian12,Probst Kristina12,Niehoff Anja34,Belluoccio Daniele56,Van den Bergen Jocelyn57,Brachvogel Bent124ORCID

Affiliation:

1. Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Medical Faculty, University of Cologne, Cologne, Germany

2. Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany

3. Institute of Biomechanics and Orthopaedics, German Sport University Cologne, Cologne, Germany

4. Cologne Center for Musculoskeletal Biomechanics (CCMB), University of Cologne, Cologne, Germany

5. Murdoch Children's Research Institute, University of Melbourne, Parkville, Victoria, Australia

6. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia

7. Department of Pediatrics, University of Melbourne, Parkville, Victoria, Australia

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 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.

Funder

Deutsche Forschungsgemeinschaft

Universität zu Köln

Publisher

The Company of Biologists

Subject

Developmental Biology,Molecular Biology

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