Hox D genes and the fin-to-limb transition: Insights from fish studies

Genes in the 5' extremity of the HoxD cluster encode DNA-binding transcription factors essential for development of the autopod and digits, regulating primarily gene expression and, consequently, morphogenesis and skeletal differentiation. Comparative studies focused on their expression and regulation have led to the idea that evolution of a bimodal regulation of the HoxD cluster, mainly due to the activation of cis-regulatory units in the centromeric side of the cluster, was a fundamental mechanism that potentiated the fin-to-limb transition in vertebrates. In addition, functional assays demonstrated that increased levels of 5'HoxD genes stimulate the production of additional endochondral bone, while repressing the formation of dermal skeleton distally. Other data have come to light in recent years suggesting that these genes may interfere directly with the production of dermal skeleton components in fish and with the activity of cis-regulatory units involved in the formation of autopod and digits. Finally, increasing evidences suggest that the role of HoxD genes in fin evolution may relate to their ability to change the fate of distal mesenchymal cells conducting them to differentiate into endochondral bone rather than in dermal skeleton. Here, we trace the history of the research concerning the involvement of HoxD genes in the fin-to-limb transition in vertebrates. To this end, we discuss three interconnected topics that have benefited from profound advances in recent years due to comparative analyses and functional assays performed using fish species: (a) comparative HoxD genes expression; (b) comparative HoxD gene transcriptional regulation; and (c) functional characterization of 5'HoxD genes.