Hoxa2 and the control of chondrogenesis : insights from a gain-of-function model

This work addresses the relationship between the activity of Hoxa2 and chondrogenesis. Hoxa2 is a homeotic gene known to pattern embryonic territories, but its expression ceases once chondrogenic differentiation gets started. Using transgenic mice ectopically expressing Hoxa2 all along chondrogenesis and applying biological markers, protein immunodetection, histological and imaging techniques, we found that Hoxa2 alters the mesenchymal-to-chondrocyte differentiation step, inhibiting the chondrogenic factors Bmp7, Bmpr1a, Nkx3-2, Pax9, Sox6, Sox9 and Wnt5a. We further found a direct DNA binding site for Hoxa2 on the 3’ side of the Sox9 coding sequence. As a consequence, Hoxa2 misregulation in mice induces a cervical lordosis and a proportionate short stature phenotype mimicking human idiopathic conditions. Together, our results give insights for understanding proportionate short stature pathogenesis and reveal molecular mechanisms linking the activity of a Hox protein, Hoxa2, and its negative impact on endochondral skeleton development.(SBIM 3) -- UCL, 201