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

Abstract

Summary 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.

Revelation of the Genetic Basis for Convergent Innovative Anal Fin Pigmentation Patterns in Cichlid Fishes

“…This difference could be due to the effect of lineage-specific position related transcripts that were not ruled out based on our strategy. However, this explanation is unlikely, considering the very closely related genetic background in cichlid fishes (Baldo et al 2011; Brawand et al 2014) and the relatively conservative fin developmental constraint (Maxwell & Wilson 2013; Paço & Freitas 2017). In addition, after position effect controlling, we observed similar numbers of up-regulated DE transcripts between egg-spots and the blotch, suggesting that the comparison strategy was not the issue.…”

“…Therefore, we corrected the position effect for egg-spots using position genes retrieved from C. macrops . Considering the very closely related genetic background in cichlid fishes (Baldo et al 2011; Brawand et al 2014) and the conservative fin development constraint (Maxwell & Wilson 2013; Paço & Freitas 2017), the effect of species-specific position genes should be small, and thus, we can get the egg-spots candidate genes to the largest extant. In addition, for finding common genes between the blotch and egg-spots, the comparison itself has already perfectly corrected the position effect considering their different locations on the anal fin (Figure 1).…”

Problems in Fish-to-Tetrapod Transition: Genetic Expeditions Into Old Specimens

“…Also, the repetitive excisions of the AF, which is critical to develop fin rays, from the developing pectoral fin, extended the size of the endochondral disk distally (Yano et al, 2012 ). Summarizing all data leads us to a novel hypothesis—the developmental program between dermal and endochondral programs are interchangeable and the dermal genetic network has been replaced by the endochondral network in appendage evolution (Nakamura et al, 2016 ; Tulenko et al, 2016 , 2017 ; Paço and Freitas, 2018 ; Figure 3E ). Given that LPM cells contribute to lepidotrichia, LPM cells that express hoxa13 genes are most likely to differentiate into dermal fin rays in fish, whereas LPM cells that experience hoxa13 and d13 develop endochondral digits in tetrapods.…”

Regulation of vertebrate forelimb development and wing reduction in the flightless emu

“…The molecular changes underlying the fin-to-limb transition are proposed to have occurred through cooption and altered regulation of the collinear axial HOX gene expression domains, and subsequent downstream patterning factors. 92 For example, investigations in fin buds of the lobe-finned lungfish show tetrapod-conserved expression of hoxa13, hoxd13, hand2, and gremlin, albeit with displaced expression domains corresponding to their postaxial fin radials. 12 Distal expansion of HOX expression domains are additionally correlated with the evolution of the autopod in terrestrial vertebrates.…”