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Clifford J Tabin - One of the best experts on this subject based on the ideXlab platform.
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developmental biology hox timing determines Limb placement
Current Biology, 2019Co-Authors: John J Young, Phil Grayson, Clifford J TabinAbstract:Summary Hox genes are known to determine vertebral identity along with being required for normal Limb Patterning. A new study now finds that differential expression timing of Hox genes in the lateral plate mesoderm determines Limb placement as well.
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Unique pelvic fin in a tetrapod-like fossil fish, and the evolution of Limb Patterning
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Jonathan E. Jeffery, Clifford J Tabin, Glenn W. Storrs, Timothy Holland, Per E. AhlbergAbstract:All living tetrapods have a one-to-two branching pattern in the embryonic proximal Limb skeleton, with a single element at the base of the Limb (the humerus or femur) that articulates distally with two parallel radials (the ulna and radius or the tibia and fibula). This pattern is also seen in the fossilized remains of stem-tetrapods, including the fishlike members of the group, in which despite the absence of digits, the proximal parts of the fin skeleton clearly resemble those of later tetrapods. However, little is known about the developmental mechanisms that establish and canalize this highly conserved pattern. We describe the well-preserved pelvic fin skeleton of Rhizodus hibberti, a Carboniferous sarcopterygian (lobe-finned) fish, and member of the tetrapod stem group. In this specimen, three parallel radials, each robust with a distinct morphology, articulate with the femur. We review this unexpected morphology in a phylogenetic and developmental context. It implies that the developmental Patterning mechanisms seen in living tetrapods, now highly constrained, evolved from mechanisms flexible enough to accommodate variation in the zeugopod (even between pectoral and pelvic fins), while also allowing each element to have a unique morphology.
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molecular anatomy of the developing Limb in the coqui frog eleutherodactylus coqui
Evolution & Development, 2011Co-Authors: Joshua B Gross, James Hanken, Ryan Kerney, Clifford J TabinAbstract:SUMMARY The vertebrate Limb demonstrates remark- able similarity in basic organization across phylogenetically disparate groups. To gain further insight into how this mor- phological similarity is maintained in different developmental contexts, we explored the molecular anatomy of size-reduced embryos of the Puerto Rican coqufrog, Eleutherodactylus coqui. This animal demonstrates direct development, a life- history strategy marked by rapid progression from egg to adult and absence of a free-living, aquatic larva. Nonethe- less, coqu´o exhibits a basal anuran Limb structure, with four toes on the foreLimb and five toes on the hind Limb. We in- vestigated the extent to which coquLimb bud development conforms to the model of Limb development derived from am- niote studies. Toward this end, we characterized dynamic pat- terns of expression for 13 critical Patterning genes across three principle stages of Limb development. As expected, most genes demonstrate expression patterns that are es- sentially unchanged compared to amniote species. For ex- ample, we identified an EcFgf8-expression domain within the apical ectodermal ridge (AER). This expression pattern de- fines a putatively functional AER signaling domain, despite the absence of a morphological ridge in coqu´o embryos. However, two genes, EcMeis2 and EcAlx4, demonstrate al- tered domains of expression, which imply a potential shift in gene function between coqufrogs and amniote model sys- tems. Unexpectedly, several genes thought to be critical for Limb Patterning in other systems, including EcFgf4, EcWnt3a, EcWnt7a, and EcGremlin, demonstrated no evident expres- sion pattern in the Limb at the three stages we analyzed. The absence of EcFgf4 and EcWnt3a expression during Limb Patterning is perhaps not surprising, given that neither gene is critical for proper Limb development in the mouse, based on knockout and expression analyses. In contrast, absence of EcWnt7a and EcGremlin is surprising, given that expres- sion of these molecules appears to be absolutely essential in all other model systems so far examined. Although this analysis substantiates the existence of a core set of an- cient Limb-Patterning molecules, which likely mediate iden- tical functions across highly diverse vertebrate forms, it also reveals remarkable evolutionary flexibility in the genetic con- trol of a conserved morphological pattern across evolutionary time.
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a reevaluation of x irradiation induced phocomelia and proximodistal Limb Patterning
Nature, 2009Co-Authors: Jenna L Galloway, Irene Delgado, Maria A Ros, Clifford J TabinAbstract:The congenital disorder phocomelia is a rare Limb malformation that became more familiar in the 1960s as a side effect of the use thalidomide in pregnancy. Phocomelia is mimicked in developing chick Limb buds exposed to X-irradiation, and studies of the chick model provided important evidence for the long-established progress zone model of Limb development, in which fibroblast growth factor produced by the apical ectoderm ridge directs cell fate. New work, involving molecular analysis and lineage tracing, shows that X-irradiation-induced phocomelia is not a Patterning defect as was thought, but results from a time-dependent loss of skeletal progenitors. This finding challenges the current model of phocomelia aetiology as well as the predictions of the progress zone model. The condition of phocomelia, a human birth defect in which the long bones are shorter than normal, is mimicked in developing chick Limb buds exposed to X-rays. Studies of X-irradiation-induced phocomelia have served as evidence supporting the 'progress zone' model of Limb Patterning. Here, X-irradiation-induced phocomelia is shown not to be a Patterning defect at all; rather, it results from a time-dependent loss of skeletal progenitors. Phocomelia is a devastating, rare congenital Limb malformation in which the long bones are shorter than normal, with the upper portion of the Limb being most severely affected. In extreme cases, the hands or fingers are attached directly to the shoulder and the most proximal elements (those closest to the shoulder) are entirely missing. This disorder, previously known in both autosomal recessive and sporadic forms, showed a marked increase in incidence in the early 1960s due to the tragic toxicological effects of the drug thalidomide, which had been prescribed as a mild sedative1,2. This human birth defect is mimicked in developing chick Limb buds exposed to X-irradiation3,4,5. Both X-irradiation5 and thalidomide-induced phocomelia5,6 have been interpreted as Patterning defects in the context of the progress zone model, which states that a cell’s proximodistal identity is determined by the length of time spent in a distal Limb region termed the ‘progress zone’7. Indeed, studies of X-irradiation-induced phocomelia have served as one of the two major experimental lines of evidence supporting the validity of the progress zone model. Here, using a combination of molecular analysis and lineage tracing in chick, we show that X-irradiation-induced phocomelia is fundamentally not a Patterning defect, but rather results from a time-dependent loss of skeletal progenitors. Because skeletal condensation proceeds from the shoulder to fingers (in a proximal to distal direction), the proximal elements are differentially affected in Limb buds exposed to radiation at early stages. This conclusion changes the framework for considering the effect of thalidomide and other forms of phocomelia, suggesting the possibility that the aetiology lies not in a defect in the Patterning process, but rather in progenitor cell survival and differentiation. Moreover, molecular evidence that proximodistal Patterning is unaffected after X-irradiation does not support the predictions of the progress zone model.
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classic Limb Patterning models and the work of dennis summerbell
Development, 2008Co-Authors: Jenna L Galloway, Clifford J TabinAbstract:Dennis Summerbell was a leading contributor to our understanding of Limb Patterning prior to the advent of molecular biology. He published several groundbreaking papers, including one that developed a key model for Patterning the Limb from the shoulder to the fingertips and another that presented the co-discovery of the effect of retinoids on Limb morphogenesis. He brought detailed quantitative analyses to bear on these studies, as highlighted in two of his insightful papers published in the Journal of Embryology and Experimental Morphology , in which he provided elegant models that, today, remain relevant to Limb Patterning, as well as to many disciplines of developmental biology.
Alexandra L Joyner - One of the best experts on this subject based on the ideXlab platform.
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Limb anterior posterior polarity integrates activator and repressor functions of gli2 as well as gli3
Developmental Biology, 2012Co-Authors: Megan Bowers, Liane Eng, Zhimin Lao, Rowena Turnbull, Xiaozhong Bao, Elyn Riedel, Susan Mackem, Alexandra L JoynerAbstract:Anterior-posterior (AP) Limb Patterning is directed by sonic hedgehog (SHH) signaling from the posteriorly located zone of polarizing activity (ZPA). GLI3 and GLI2 are the transcriptional mediators generally utilized in SHH signaling, and each can function as an activator (A) and repressor (R). Although GLI3R has been suggested to be the primary effector of SHH signaling during Limb AP Patterning, a role for GLI3A or GLI2 has not been fully ruled out, nor has it been determined whether Gli3 plays distinct roles in Limb development at different stages. By conditionally removing Gli3 in the Limb at multiple different time points, we uncovered four Gli3-mediated functions in Limb development that occur at distinct but partially over-lapping time windows: AP Patterning of the proximal Limb, AP Patterning of the distal Limb, regulation of digit number and bone differentiation. Furthermore, by removing Gli2 in Gli3 temporal conditional knock-outs, we uncovered an essential role for Gli2 in providing the remaining posterior Limb Patterning seen in Gli3 single mutants. To test whether GLIAs or GLIRs regulate different aspects of AP Limb Patterning and/or digit number, we utilized a knock-in allele in which GLI1, which functions solely as an activator, is expressed in place of the bifunctional GLI2 protein. Interestingly, we found that GLIAs contribute to AP Patterning specifically in the posterior Limb, whereas GLIRs predominantly regulate anterior Patterning and digit number. Since GLI3 is a more effective repressor, our results explain why GLI3 is required only for anterior Limb Patterning and why GLI2 can compensate for GLI3A in posterior Limb Patterning. Taken together, our data suggest that establishment of a complete range of AP positional identities in the Limb requires integration of the spatial distribution, timing, and dosage of GLI2 and GLI3 activators and repressors.
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dynamic changes in the response of cells to positive hedgehog signaling during mouse Limb Patterning
Cell, 2004Co-Authors: Sohyun Ahn, Alexandra L JoynerAbstract:In the vertebrate Limb, the posteriorly located zone of polarizing activity (ZPA) regulates digit identity through the morphogen Sonic Hedgehog (Shh). By genetically marking Shh-responding cells in mice, we have addressed whether the cumulative influence of positive Shh signaling over time and space reflects a linear gradient of Shh responsiveness and whether Shh could play additional roles in Limb Patterning. Our results show that all posterior Limb mesenchyme cells, as well as the ectoderm, respond to Shh from the ZPA and become the bone, muscle, and skin of the posterior Limb. Further, the readout of Shh activator function integrated over time and space does not display a stable and linear gradient along the A-P axis, as in a classical morphogen view. Finally, by fate mapping Shh-responding cells in Gli2 and Gli3 mutant Limbs, we demonstrate that a specific level of positive Hh signaling is not required to specify digit identities.
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the mouse engrailed 1 gene and ventral Limb Patterning
Nature, 1996Co-Authors: Cynthia A Loomis, Esther Harris, Jacques Michaud, Wolfgang Wurst, Mark C Hanks, Alexandra L JoynerAbstract:During vertebrate Limb development, positional information must be specified along three distinct axes. Although much progress has been made in our understanding of the molecular interactions involved in anterior-posterior and proximal-distal Limb Patterning, less is known about dorsal-ventral Patterning. The genes Wnt-7a and Lmx-1, which are expressed in dorsal Limb ectoderm and mesoderm, respectively, are thought to be important regulators of dorsal Limb differentiation. Whether a complementary set of molecules controls ventral Limb development has not been clear. Here we report that Engrailed-1, a homeodomain-containing transcription factor expressed in embryonic ventral Limb ectoderm, is essential for ventral Limb Patterning. Loss of Engrailed-1 function in mice results in dorsal transformations of ventral paw structures, and in subtle alterations along the proximal-distal Limb axis. Engrailed-1 seems to act in part by repressing dorsal differentiation induced by Wnt-7a, and is essential for proper formation of the apical ectodermal ridge.
Ryan Kerney - One of the best experts on this subject based on the ideXlab platform.
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early Limb Patterning in the direct developing salamander plethodon cinereus revealed by sox9 and col2a1
Evolution & Development, 2018Co-Authors: Ryan Kerney, James Hanken, David C BlackburnAbstract:Direct-developing amphibians form Limbs during early embryonic stages, as opposed to the later, often postembryonic Limb formation of metamorphosing species. Limb Patterning is dramatically altered in direct-developing frogs, but little attention has been given to direct-developing salamanders. We use expression patterns of two genes, sox9 and col2a1, to assess skeletal Patterning during embryonic Limb development in the direct-developing salamander Plethodon cinereus. Limb Patterning in P. cinereus partially resembles that described in other urodele species, with early formation of digit II and a generally anterior-to-posterior formation of preaxial digits. Unlike other salamanders described to date, differentiation of preaxial zeugopodial cartilages (radius/tibia) is not accelerated in relation to the postaxial cartilages, and there is no early differentiation of autopodial elements in relation to more proximal cartilages. Instead, digit II forms in continuity with the ulnar/fibular arch. This amniote-like connectivity to the first digit that forms may be a consequence of the embryonic formation of Limbs in this direct-developing species. Additionally, and contrary to recent models of amphibian digit identity, there is no evidence of vestigial digits. This is the first account of gene expression in a plethodontid salamander and only the second published account of embryonic Limb Patterning in a direct-developing salamander species.
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molecular anatomy of the developing Limb in the coqui frog eleutherodactylus coqui
Evolution & Development, 2011Co-Authors: Joshua B Gross, James Hanken, Ryan Kerney, Clifford J TabinAbstract:SUMMARY The vertebrate Limb demonstrates remark- able similarity in basic organization across phylogenetically disparate groups. To gain further insight into how this mor- phological similarity is maintained in different developmental contexts, we explored the molecular anatomy of size-reduced embryos of the Puerto Rican coqufrog, Eleutherodactylus coqui. This animal demonstrates direct development, a life- history strategy marked by rapid progression from egg to adult and absence of a free-living, aquatic larva. Nonethe- less, coqu´o exhibits a basal anuran Limb structure, with four toes on the foreLimb and five toes on the hind Limb. We in- vestigated the extent to which coquLimb bud development conforms to the model of Limb development derived from am- niote studies. Toward this end, we characterized dynamic pat- terns of expression for 13 critical Patterning genes across three principle stages of Limb development. As expected, most genes demonstrate expression patterns that are es- sentially unchanged compared to amniote species. For ex- ample, we identified an EcFgf8-expression domain within the apical ectodermal ridge (AER). This expression pattern de- fines a putatively functional AER signaling domain, despite the absence of a morphological ridge in coqu´o embryos. However, two genes, EcMeis2 and EcAlx4, demonstrate al- tered domains of expression, which imply a potential shift in gene function between coqufrogs and amniote model sys- tems. Unexpectedly, several genes thought to be critical for Limb Patterning in other systems, including EcFgf4, EcWnt3a, EcWnt7a, and EcGremlin, demonstrated no evident expres- sion pattern in the Limb at the three stages we analyzed. The absence of EcFgf4 and EcWnt3a expression during Limb Patterning is perhaps not surprising, given that neither gene is critical for proper Limb development in the mouse, based on knockout and expression analyses. In contrast, absence of EcWnt7a and EcGremlin is surprising, given that expres- sion of these molecules appears to be absolutely essential in all other model systems so far examined. Although this analysis substantiates the existence of a core set of an- cient Limb-Patterning molecules, which likely mediate iden- tical functions across highly diverse vertebrate forms, it also reveals remarkable evolutionary flexibility in the genetic con- trol of a conserved morphological pattern across evolutionary time.
Philip A Beachy - One of the best experts on this subject based on the ideXlab platform.
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hedgehog regulated processing of gli3 produces an anterior posterior repressor gradient in the developing vertebrate Limb
Cell, 2000Co-Authors: Baolin Wang, John F Fallon, Philip A BeachyAbstract:Ci/Gli zinc finger proteins mediate the transcriptional effects of Hedgehog protein signals. In Drosophila, Ci action as transcriptional repressor or activator is contingent upon Hedgehog-regulated, PKA-dependent proteolytic processing. We demonstrate that PKA-dependent processing of vertebrate Gli3 in developing Limb similarly generates a potent repressor in a manner antagonized by apparent long-range signaling from posteriorly localized Sonic hedgehog protein. The resulting anterior/posterior Gli3 repressor gradient can be perturbed by mutations of Gli3 in human genetic syndromes or by misregulation of Gli3 processing in the chicken mutant talpid2, producing a range of Limb Patterning malformations. The high relative abundance and potency of Gli3 repressor suggest specialization of Gli3 and its products for negative Hedgehog pathway regulation.
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Limb Patterning activity and restricted posterior localization of the amino terminal product of sonic hedgehog cleavage
Current Biology, 1995Co-Authors: Alric Lopezmartinez, Maria A Ros, Philip A Beachy, David T Chang, Chin Chiang, Jeffery A Porter, Kay B Simandl, John F FallonAbstract:Abstract Background: Sonic hedgehog (Shh), a vertebrate homolog of the Drosophila segment polarity gene hedgehog (hh), has been implicated in Patterning of the developing chick Limb. Such a role is suggested by the restricted expression of Shh along the posterior Limb bud margin, and by the observation that heterologous cells expressing Shh have Limb-polarizing activity resembling that of cells from the polarizing region of the posterior Limb bud margin. It has not been demonstrated, however, that the Sonic hedgehog protein (SHH) alone is sufficient for Limb Patterning. SHH has been shown to undergo autoproteolytic cleavage in vitro, yielding two smaller products. It is of interest, therefore, to determine whether processing of SHH occurs in the developing Limb and how such processing influences the function of SHH. Results We demonstrate that SHH is proteolytically processed in developing chick Limbs. Grafts of cells expressing SHH protein variants that correspond to individual cleavage products demonstrate that the ability to induce patterned gene expression and to impose morphological pattern upon the Limb bud is limited to the amino-terminal product (SHH-N) of SHH proteolytic cleavage. We also demonstrate that bacterially synthesized and purified SHH-N, released from implanted beads, is sufficient for Limb-Patterning activity. Finally, we show that the endogenous amino-terminal cleavage product is tightly localized to the posterior margin of the Limb bud. Conclusion Our data show that, of the two cleavage products resulting from SHH autoproteolysis, SHH-N expressed in grafted heterologous cells or supplied in purified form is sufficient to impose pattern upon the developing Limb. Moreover, the restricted localization of the endogenous amino-terminal SHH cleavage product to the posterior border of the chick Limb bud makes it unlikely that its Patterning activity results from it being distributed in a broad gradient across the antero-posterior axis. More consistent with the observed localization is a model in which the amino-terminal SHH cleavage product exerts its Patterning effects by local induction in or near the polarizing region, initiating a cascade of gene expression that ultimately extends across the developing Limb.
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products genetic linkage and Limb Patterning activity of a murine hedgehog gene
Development, 1994Co-Authors: David T Chang, John F Fallon, Chin Chiang, A Lopez, D P Von Kessler, B K Simandl, R Zhao, Michael F Seldin, Philip A BeachyAbstract:The hedgehog (hh) segmentation gene of Drosophila melanogaster encodes a secreted signaling protein that functions in the Patterning of larval and adult structures. Using low stringency hybridization and degenerate PCR primers, we have isolated complete or partial hh-like sequences from a range of invertebrate species including other insects, leech and sea urchin. We have also isolated three mouse and two human DNA fragments encoding distinct hh-like sequences. Our studies have focused upon Hhg-1, a mouse gene encoding a protein with 46% amino acid identity to hh. The Hhg-1 gene, which corresponds to the previously described vhh-1 or sonic class, is expressed in the notochord, ventral neural tube, lung bud, hindgut and posterior margin of the Limb bud in developing mouse embryos. By segregation analysis the Hhg-1 gene has been localized to a region in proximal chromosome 5, where two mutations affecting mouse Limb development previously have been mapped. In Drosophila embryos, ubiquitous expression of the Hhg-1 gene yields effects upon gene expression and cuticle pattern similar to those observed for the Drosophila hh gene. We also find that cultured quail cells transfected with a Hhg-1 expression construct can induce digit duplications when grafted to anterior or mid-distal but not posterior borders within the developing chick Limb; more proximal Limb element duplications are induced exclusively by mid-distal grafts. Both in transgenic Drosophila embryos and in transfected quail cells, the Hhg-1 protein product is cleaved to yield two stable fragments from a single larger precursor. The significance of Hhg-1 genetic linkage, Patterning activity and proteolytic processing in Drosophila and chick embryos is discussed.
James Hanken - One of the best experts on this subject based on the ideXlab platform.
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environmental oxygen exposure allows for the evolution of interdigital cell death in Limb Patterning
Developmental Cell, 2019Co-Authors: Ingrid Rosenburg Cordeiro, James Hanken, Kaori Kabashima, Haruki Ochi, Keijiro Munakata, Chika Nishimori, Mara Laslo, Mikiko TanakaAbstract:Summary Amphibians form fingers without webbing by differential growth between digital and interdigital regions. Amniotes, however, employ interdigital cell death (ICD), an additional mechanism that contributes to a greater variation of Limb shapes. Here, we investigate the role of environmental oxygen in the evolution of ICD in tetrapods. While cell death is restricted to the Limb margin in amphibians with aquatic tadpoles, Eleutherodactylus coqui , a frog with terrestrial-direct-developing eggs, has cell death in the interdigital region. Chicken requires sufficient oxygen and reactive oxygen species to induce cell death, with the oxygen tension profile itself being distinct between the Limbs of chicken and Xenopus laevis frogs. Notably, increasing blood vessel density in X. laevis Limbs, as well as incubating tadpoles under high oxygen levels, induces ICD. We propose that the oxygen available to terrestrial eggs was an ecological feature crucial for the evolution of ICD, made possible by conserved autopod-Patterning mechanisms.
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early Limb Patterning in the direct developing salamander plethodon cinereus revealed by sox9 and col2a1
Evolution & Development, 2018Co-Authors: Ryan Kerney, James Hanken, David C BlackburnAbstract:Direct-developing amphibians form Limbs during early embryonic stages, as opposed to the later, often postembryonic Limb formation of metamorphosing species. Limb Patterning is dramatically altered in direct-developing frogs, but little attention has been given to direct-developing salamanders. We use expression patterns of two genes, sox9 and col2a1, to assess skeletal Patterning during embryonic Limb development in the direct-developing salamander Plethodon cinereus. Limb Patterning in P. cinereus partially resembles that described in other urodele species, with early formation of digit II and a generally anterior-to-posterior formation of preaxial digits. Unlike other salamanders described to date, differentiation of preaxial zeugopodial cartilages (radius/tibia) is not accelerated in relation to the postaxial cartilages, and there is no early differentiation of autopodial elements in relation to more proximal cartilages. Instead, digit II forms in continuity with the ulnar/fibular arch. This amniote-like connectivity to the first digit that forms may be a consequence of the embryonic formation of Limbs in this direct-developing species. Additionally, and contrary to recent models of amphibian digit identity, there is no evidence of vestigial digits. This is the first account of gene expression in a plethodontid salamander and only the second published account of embryonic Limb Patterning in a direct-developing salamander species.
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molecular anatomy of the developing Limb in the coqui frog eleutherodactylus coqui
Evolution & Development, 2011Co-Authors: Joshua B Gross, James Hanken, Ryan Kerney, Clifford J TabinAbstract:SUMMARY The vertebrate Limb demonstrates remark- able similarity in basic organization across phylogenetically disparate groups. To gain further insight into how this mor- phological similarity is maintained in different developmental contexts, we explored the molecular anatomy of size-reduced embryos of the Puerto Rican coqufrog, Eleutherodactylus coqui. This animal demonstrates direct development, a life- history strategy marked by rapid progression from egg to adult and absence of a free-living, aquatic larva. Nonethe- less, coqu´o exhibits a basal anuran Limb structure, with four toes on the foreLimb and five toes on the hind Limb. We in- vestigated the extent to which coquLimb bud development conforms to the model of Limb development derived from am- niote studies. Toward this end, we characterized dynamic pat- terns of expression for 13 critical Patterning genes across three principle stages of Limb development. As expected, most genes demonstrate expression patterns that are es- sentially unchanged compared to amniote species. For ex- ample, we identified an EcFgf8-expression domain within the apical ectodermal ridge (AER). This expression pattern de- fines a putatively functional AER signaling domain, despite the absence of a morphological ridge in coqu´o embryos. However, two genes, EcMeis2 and EcAlx4, demonstrate al- tered domains of expression, which imply a potential shift in gene function between coqufrogs and amniote model sys- tems. Unexpectedly, several genes thought to be critical for Limb Patterning in other systems, including EcFgf4, EcWnt3a, EcWnt7a, and EcGremlin, demonstrated no evident expres- sion pattern in the Limb at the three stages we analyzed. The absence of EcFgf4 and EcWnt3a expression during Limb Patterning is perhaps not surprising, given that neither gene is critical for proper Limb development in the mouse, based on knockout and expression analyses. In contrast, absence of EcWnt7a and EcGremlin is surprising, given that expres- sion of these molecules appears to be absolutely essential in all other model systems so far examined. Although this analysis substantiates the existence of a core set of an- cient Limb-Patterning molecules, which likely mediate iden- tical functions across highly diverse vertebrate forms, it also reveals remarkable evolutionary flexibility in the genetic con- trol of a conserved morphological pattern across evolutionary time.