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Abstract
Eph receptors and ephrins exhibit complex and highly dynamic expression patterns during embryonic development. In addition, changes in their expression levels are often associated with pathological situations in adults. Yet, little is known about the mechanisms regulating their expression. Here we report that the expression of ephrin-B1 is controlled by a feedback loop involving posttranscriptional regulatory mechanisms. We observed that the EfnB1 3′ untranslated region (3′-UTR) confers instability to mRNA transcripts, and we identified miR-124 as a posttranscriptional repressor of EfnB1 expression. Furthermore, we showed that miR-124 is itself regulated by ephrin-B1 reverse signaling, thus revealing the existence of a mutually repressive interaction between ephrin-B1 and this microRNA (miRNA). Lastly, we demonstrated the relevance of this mutual inhibition for neuronal differentiation. Our results suggest that miRNAs could be important effectors of Eph/ephrin signaling to refine domains of expression and to regulate function.
Supplemental material for this article may be found at http://mcb.asm.org/.
The pENTR-U6-miR-124 construct and LNA-124 were generous gifts from F. H. Gage (Salk Institute) and J. Cavaillé (LBME, France), respectively. J. Torrisani (IMMR, France) made the miR-195 DNA construct. The AUF-1- and HuR-encoding plasmids and primer sequences were generous gifts from D. Morello (CBD, France). The ephrin-B1-GFP fusion construct was a kind gift from J. Chen (Vanderbilt University). The pCAGGS-GFP construct was kindly provided by L. Nguyen (CNCM, Belgium). Images were generated in the Toulouse Rio Imaging facility. We thank our laboratory colleagues for critical reading of the manuscript.
This work was supported by a career development award from the HFSPO and an ATIP from the CNRS, both awarded to A.D. D.N.A., T.J., and A.D. are supported by the CNRS, while A.B. is supported by the HFSPO.