This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Paired appendages—the pectoral and pelvic fins of fishes and the forelimbs and hindlimbs of tetrapods—were a major innovation in vertebrate evolution. Their emergence greatly expanded the ways vertebrates could move through their environments and ultimately provided the developmental foundation for the evolution of limbs.
Yet how the genetic system responsible for building paired appendages was assembled during evolution remains an unresolved question. Hox genes are central regulators of vertebrate body patterning. In particular, HoxA and HoxD paralog groups 9–13 are known to control the later patterning of both fish fins and tetrapod limbs.
This deeply conserved role has suggested a connection between the Hox code that specifies positions along the main body axis and the developmental program that patterns paired appendages. However, direct functional evidence showing that posterior Hox genes are required at the very earliest stages of hind appendage formation has been limited. A research group led by associate professor Akinori Kawamura of the Graduate School of Science and Engineering, Saitama University, working with researchers from Tottori University, the National Institute of Genetics, the National Institute for Basic Biology and the Exploratory Research Center on Life and Living Systems, aimed to determine whether posterior Hox genes are required for the initial establishment of hind appendage progenitor cells and whether this function is conserved across distantly related vertebrates.
Using zebrafish carrying combinations of Hox gene mutations, fluorescent reporter lines that visualize developing pelvic fin progenitors, skeletal imaging and CRISPR-Cas9-mediated disruption of Hox genes in the Iberian ribbed newt, the team revealed an evolutionarily conserved requirement for Hox9–10 genes during the earliest stages of hind appendage formation. The study is published in the Proceedings of the National Academy of Sciences. In zebrafish, the researchers found that simultaneously disrupting five HoxA/D paralog group 9–10 genes—hoxa9a, hoxa9b, hoxa10b, hoxd9a, and hoxd10a—resulted in the complete loss of pelvic fins.
Fluorescent reporter analyses using markers associated with pelvic fin progenitor cells further showed that the characteristic bilateral progenitor populations could no longer be detected in these mutants, indicating that HoxA/D PG9–10 genes act before morphologically recognizable pelvic fin buds form. A hoxa10b reporter also marked cells in the presumptive pelvic fin field before fin bud formation, further supporting an early role for these genes. The researchers then asked whether this function extends beyond ray-finned fishes.
In the Iberian ribbed newt, a lobe-finned vertebrate lineage, they simultaneously disrupted all seven Hox9–10 paralogs using CRISPR-Cas9. Animals showing hindlimb loss also displayed corresponding loss or marked reduction of Prdm16 expression in prospective hindlimb-forming regions. Together, the zebrafish and newt experiments indicate that the requirement for Hox9–10 genes in establishing hind appendage progenitors predates the evolutionary divergence of these distantly related vertebrate lineages.
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