Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10682-6. doi: 10.1073/pnas.1300592110. Epub 2013 May 14.
Patterning of the vertebrate skeleton requires the coordinated activity of Hox genes. In particular, Hox10 proteins are essential to set the transition from thoracic to lumbar vertebrae because of their rib-repressing activity. In snakes, however, the thoracic region extends well into Hox10-expressing areas of the embryo, suggesting that these proteins are unable to block rib formation. Here, we show that this is not a result of the loss of rib-repressing properties by the snake proteins, but rather to a single base pair change in a Hox/Paired box (Pax)-responsive enhancer, which prevents the binding of Hox proteins. This polymorphism is also found in Paenungulata, such as elephants and manatees, which have extended rib cages. In vivo, this modified enhancer failed to respond to Hox10 activity, supporting its role in the extension of rib cages. In contrast, the enhancer could still interact with Hoxb6 and Pax3 to promote rib formation. These results suggest that a polymorphism in the Hox/Pax-responsive enhancer may have played a role in the evolution of the vertebrate spine by differently modulating its response to rib-suppressing and rib-promoting Hox proteins.
脊椎动物骨骼的模式形成需要 Hox 基因的协调活动。特别是，Hox10 蛋白对于从胸腰椎的转变至关重要，因为它们具有肋骨抑制活性。然而，在蛇中，胸区延伸到胚胎中表达 Hox10 的区域，这表明这些蛋白质无法阻止肋骨形成。在这里，我们表明，这不是蛇蛋白失去肋骨抑制特性的结果，而是由于 Hox/Paired 盒（Pax）反应增强子中的单个碱基对变化，从而阻止了 Hox 蛋白的结合。这种多态性也存在于 Paenungulata 中，例如大象和海牛，它们具有扩展的胸腔。在体内，这种修饰后的增强子无法对 Hox10 活性做出反应，支持其在扩展胸腔中的作用。相比之下，该增强子仍然可以与 Hoxb6 和 Pax3 相互作用以促进肋骨形成。这些结果表明，Hox/Pax 反应增强子中的多态性可能通过不同地调节其对抑制肋骨和促进肋骨的 Hox 蛋白的反应，在脊椎动物脊柱的进化中发挥了作用。
