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The origin and diversification of appendage types is a central question in vertebrate evolution. Understanding the genetic mechanisms that underlie fin and limb development can reveal relationships between different appendages. Here we demonstrate, using chemical genetics, a mutually agonistic interaction between Fgf and Shh genes in the developing dorsal fin of the channel catfish, Ictalurus punctatus . We also find that Fgf8 and Shh orthologs are expressed in the apical ectodermal ridge and zone of polarizing activity, respectively, in the median fins of representatives from other major vertebrate lineages. These findings demonstrate the importance of this feedback loop in median fins and offer developmental evidence for a median fin-first scenario for vertebrate paired appendage origins. 

The transformation of paired fins into tetrapod limbs is one of the most intensively scrutinized events in animal evolution. Early anatomical and embryological datasets identified distinctive morphological regions within the appendage and posed hypotheses about how the loss, gain, and transformation of these regions could explain the observed patterns of both extant and fossil appendage diversity. These hypotheses have been put to the test by our growing understanding of patterning mechanisms that regulate formation of the appendage axes, comparisons of gene expression data from an array of phylogenetically informative taxa, and increasingly sophisticated and elegant experiments leveraging the latest molecular approaches. Together, these data demonstrate the remarkable conservation of developmental mechanisms, even across phylogenetically and morphologically disparate taxa, as well as raising new questions about the way we view homology, evolutionary novelty, and the often non-linear connection between morphology and gene expression. In this review, we present historical hypotheses regarding paired fin evolution and limb origins, summarize key aspects of central appendage patterning mechanisms in model and non-model species, address how modern comparative developmental data interface with our understanding of appendage anatomy, and highlight new approaches that promise to provide new insight into these well-traveled questions. 

Abstract The development of paired appendages was a key innovation during evolution and facilitated the aquatic to terrestrial transition of vertebrates. Largely derived from the lateral plate mesoderm (LPM), one hypothesis for the evolution of paired fins invokes derivation from unpaired median fins via a pair of lateral fin folds located between pectoral and pelvic fin territories 1 . Whilst unpaired and paired fins exhibit similar structural and molecular characteristics, no definitive evidence exists for paired lateral fin folds in larvae or adults of any extant or extinct species. As unpaired fin core components are regarded as exclusively derived from paraxial mesoderm, any transition presumes both co-option of a fin developmental programme to the LPM and bilateral duplication 2 . Here, we identify that the larval zebrafish unpaired pre-anal fin fold (PAFF) is derived from the LPM and thus may represent a developmental intermediate between median and paired fins. We trace the contribution of LPM to the PAFF in both cyclostomes and gnathostomes, supporting the notion that this is an ancient trait of vertebrates. Finally, we observe that the PAFF can be bifurcated by increasing bone morphogenetic protein signalling, generating LPM-derived paired fin folds. Our work provides evidence that lateral fin folds may have existed as embryonic anlage for elaboration to paired fins. 

Synopsis Mechanistically connecting genotypes to phenotypes is a longstanding and central mission of biology. Deciphering these connections will unite questions and datasets across all scales from molecules to ecosystems. Although high-throughput sequencing has provided a rich platform on which to launch this effort, tools for deciphering mechanisms further along the genome to phenome pipeline remain limited. Machine learning approaches and other emerging computational tools hold the promise of augmenting human efforts to overcome these obstacles. This vision paper is the result of a Reintegrating Biology Workshop, bringing together the perspectives of integrative and comparative biologists to survey challenges and opportunities in cracking the genotype to phenotype code and thereby generating predictive frameworks across biological scales. Key recommendations include promoting the development of minimum “best practices” for the experimental design and collection of data; fostering sustained and long-term data repositories; promoting programs that recruit, train, and retain a diversity of talent; and providing funding to effectively support these highly cross-disciplinary efforts. We follow this discussion by highlighting a few specific transformative research opportunities that will be advanced by these efforts. 

Salamanders and lungfishes are the only sarcopterygians (lobe-finned vertebrates) capable of paired appendage regeneration, regardless of the amputation level. Among actinopterygians (ray-finned fishes), regeneration after amputation at the fin endoskeleton has only been demonstrated in polypterid fishes (Cladistia). Whether this ability evolved independently in sarcopterygians and actinopterygians or has a common origin remains unknown. Here we combine fin regeneration assays and comparative RNA-sequencing (RNA-seq) analysis of Polypterus and axolotl blastemas to provide support for a common origin of paired appendage regeneration in Osteichthyes (bony vertebrates). We show that, in addition to polypterids, regeneration after fin endoskeleton amputation occurs in extant representatives of 2 other nonteleost actinopterygians: the American paddlefish (Chondrostei) and the spotted gar (Holostei). Furthermore, we assessed regeneration in 4 teleost species and show that, with the exception of the blue gourami (Anabantidae), 3 species were capable of regenerating fins after endoskeleton amputation: the white convict and the oscar (Cichlidae), and the goldfish (Cyprinidae). Our comparative RNA-seq analysis of regenerating blastemas of axolotl and Polypterus reveals the activation of common genetic pathways and expression profiles, consistent with a shared genetic program of appendage regeneration. Comparison of RNA-seq data from early Polypterus blastema to single-cell RNA-seq data from axolotl limb bud and limb regeneration stages shows that Polypterus and axolotl share a regeneration-specific genetic program. Collectively, our findings support a deep evolutionary origin of paired appendage regeneration in Osteichthyes and provide an evolutionary framework for studies on the genetic basis of appendage regeneration. 

The anamniote lateral line system, comprising mechanosensory neuromasts and electrosensory ampullary organs, is a useful model for investigating the developmental and evolutionary diversification of different organs and cell types. Zebrafish neuromast development is increasingly well understood, but neither zebrafish nor Xenopus is electroreceptive and our molecular understanding of ampullary organ development is rudimentary. We have used RNA-seq to generate a lateral line-enriched gene-set from late-larval paddlefish (Polyodon spathula). Validation of a subset reveals expression in developing ampullary organs of transcription factor genes critical for hair cell development, and genes essential for glutamate release at hair cell ribbon synapses, suggesting close developmental, physiological and evolutionary links between non-teleost electroreceptors and hair cells. We identify an ampullary organ-specific proneural transcription factor, and candidates for the voltage-sensing L-type Cav channel and rectifying Kv channel predicted from skate (cartilaginous fish) ampullary organ electrophysiology. Overall, our results illuminate ampullary organ development, physiology and evolution.