Résumé :
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The molecular mechanisms underlying tendon formation during vertebrate embryogenesis are still largely unknown. In Drosophila, tendon differentiation relies upon the transcription factor stripe, an Early growth response (Egr)-like transcription factor. Based on the requirement for stripe in tendon formation in Drosophila, we investigated the involvement of the homologous Egr family members, Egr1 and Egr2 in vertebrate tendon formation. We established that Egr1 and Egr2 transcripts are located in forming and differentiating limb tendons during chick and mouse embryogenesis. The secreted factor fibroblast growth factor-4 activated the expression of both Egr genes within 4 hours before the activation of the differentiation tendon markers Scleraxis, EphA4 and the collagens I, V and XII. Misexpression experiments using the chick model allowed us to establish that Egr genes are sufficient for the expression of Scleraxis and tendon-associated collagens. Analysis of embryonic limbs from mouse mutants for Egr1 or Egr2 did not exhibit major modifications in tendon formation, based on the expression of Scleraxis and collagen I, suggesting redundancy between both genes in tendon formation. Finally, we showed that Egr2 enhanced the activity of the col1a1 tendon promoter, indicating that Egr2 is part of the DNA-binding protein network involved in the regulation the col1a1 expression in tendons. The endogenous tendon expression of the Egrs, their regulation by Fgf4, their sufficiency to induce tendon gene expression and their ability to bind the tendon promoter of col1a1 all indicate that Egr genes control tendon cell differentiation by regulating Scleraxis and collagen expression. This represents a rare example of conserved regulatory function between homologous genes in invertebrates and vertebrates.
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