Evolution of Vertebrate Limb Development

Abstract

The origin and diversification of fins and limbs have long been a focus of interest to both palaeontologists and developmental biologists. Studies conducted in recent decades have resulted in enormous progress in the understanding of the genetic and developmental bases of the evolution of paired appendages in vertebrates. These discoveries in the areas of genetics and developmental biology have shed light on the mechanisms underlying the evolution of this key morphological innovation in vertebrates. In this article, recent advances in these fields and how they can provide a mechanistic explanation for the origin and evolution of paired appendages have been discussed.

Key Concepts

  • Step‐wise changes seem to be involved in the acquisition of paired fins, such as regionalisation of the lateral plate mesoderm (LPM) into the anterior and posterior LPM; sub‐division of the LPM into somatic and splanchnic layers; acquisition of expression of genes that initiate limb formation, such as Tbx4/5; and dorso‐ventral compartmentalisation of ectoderm.
  • Morphological changes during the fin‐to‐limb transition include the acquisition of the autopod and the evolutionary modification of skeletal patterns along the anterior–posterior axis.
  • The fin‐to‐limb transition seems to involve changes in transcriptional regulation of HoxA and HoxD clusters, changes in the expression of Gli3 and Shh, loss of the fin fold, and modification of the BMP‐SOX9‐WNT Turing network.
  • Changes in the activity of regulatory elements of genes known to play pivotal roles in limb development seem to be related to the morphological diversification of limbs and the loss of paired fins and limbs.

Keywords: limb; fin; evolution; vertebrates; lateral plate mesoderm

Figure 1. Models for the evolution of paired appendages in vertebrates. (a) The ‘lateral fin fold theory’, in which two paired appendages evolved from a continuous lateral fin, was proposed by Thacher ; Mivart and Balfour . (b) The ‘pelvic before pectoral fin’ model suggested that the co‐option of collinear expression of Hox (green bars) from the body axis in paired appendages originated in the pelvic appendage. In this model, pelvic Hox expression was subsequently co‐opted for the development of the pectoral appendage (Tabin and Laufer, ). (c) The ‘pectoral before pelvic fin’ model was advocated based on fossil records and on the general anterior–posterior gradient of development (Coates, ; Thorogood and Ferretti, ). (d) The molecular mechanisms of fin development in paired appendages have been proposed to be adopted from the median fins (Freitas et al.,). This view was based on the observation that Hoxd genes (green bars) were expressed in a nested manner in the developing shark median fin, as seen in the paired appendages. (e) Two alternative models for the evolution of paired appendages proposed by Ruvinsky and Gibson‐Brown highlighted the coevolution of the T‐box gene with Pitx1. Initially, an ancestral jawless vertebrate acquired a novel expression domain of Tbx4/5 (purple) in the lateral plate mesoderm at the pectoral level, and this led to the formation of the first pair of fins (top). Then two alternative scenarios were considered: the T‐box cluster underwent duplication, and Tbx4 (red) and Tbx5 (blue) were co‐expressed in a single pair of fins (left middle). Subsequently, Tbx4 (red) acquired the novel expression domain in the body wall at the pelvic level (bottom). Alternatively, Tbx4/5 (purple) acquired a novel expression domain in the posterior part of the lateral plate mesoderm (right middle), and then Tbx4/5 underwent duplication and gave rise to pectoral (blue) and pelvic fins (red) (bottom). According to this model, posteriorly expressed Pitx1 (yellow) modified the identity of the posterior/pelvic appendages together with Tbx4. (f) Schematic model for regionalisation and differentiation of the ventral mesoderm and the lateral plate mesoderm (LPM) in amphioxus, lampreys and representative gnathostomes, as proposed by Onimaru et al.. Purple, orange and light blue bars represent the pharyngeal mesoderm (ph), the anterior LPM (ALPM) and the posterior LPM (PLPM), respectively. Double‐headed arrows indicate the somatic mesodermal layer. Distribution of Tbx4/5 (purple) in amphioxus and lampreys, Tbx5 (blue) in gnathostomes, and collinear Hox genes (green bars) in lampreys and gnathostomes are indicated in each embryo. vmp, ventral mesoderm posterior to the pharynx. Schematic modified from Onimaru et al. and Tanaka . Models in panels A–F were proposed by Jarvik ; Tabin and Laufer ; Thorogood and Ferretti ; Ruvinsky and Gibson‐Brown , and Onimaru et al., respectively.
Figure 2. Expression and regulation of 5'Hox genes. (a) Schematic illustration of the early (top) and late (bottom) phases of 5'Hoxa (magenta) and 5'Hoxd (blue) genes in mouse forelimb buds. Expression patterns of 5'Hox genes were re‐drawn and modified after Dolle et al.. (b) Model for the regulatory evolution of HoxA and HoxD genes during the fin‐to‐limb transition proposed by Woltering et al.. Coloured shapes located in the 5′ and 3′ regions of each Hox gene cluster (black rectangle) indicate enhancers, and arrows indicate the interactions between these enhancers and the Hox cluster. In fish fins, this interaction may pattern the proximal (red) and distal (orange) skeletal elements. In tetrapod limbs, new enhancers have been acquired or existing ones were modified, and thereby, a novel and more distal autopodial identity may have evolved. Redrawn and modified after Woltering et al. 2014 published by PLOS licensed in accordance with the Creative Commons Attribution (CC BY) license.
Figure 3. Skeletal patterns of anterior appendages of catshark S. canicula, Eusthenopteron, Panderichthys, Tiktaalik, Acanthostega and mouse. Grey bones indicate the basal metapterygium and humerus. Note that S. canicula has tri‐basal pectoral fins. R, radius; U, ulna. Adapted from Onimaru et al.,2015, Johanson et al.,2007, Boisvert et al.,2008 and Shubin et al.,2006.
Figure 4. Schematic diagrams of expression patterns of genes involved in anterior–posterior patterning in S. canicula pectoral fin buds and mouse forelimb buds. (a) Gli3 (orange) is highly expressed in the posterior region of S. canicula pectoral fin buds. In contrast, Gli3 is highly expressed in the anterior region of murine forelimb buds. (b) The Alx4 (pink)/Pax9 (light blue) anterior domain is more extensive in S. canicula pectoral fin buds than in murine forelimb buds. (c) Skeletal pattern of S. canicula pectoral fin and mouse forelimb. Grey elements are the pro‐ and mesopterygium. Purple bones indicate the basal metapterygium/humerus. Expression patterns were re‐drawn from previous work: S. canicula (Onimaru et al.,) and mouse (Fernandez‐Teran et al.,; McGlinn et al.,; Yokoyama et al.,; Galli et al.,). See text for additional references and details.
close

References

Adachi N, Robinson M, Goolsbee A and Shubin NH (2016) Regulatory evolution of Tbx5 and the origin of paired appendages. Proceedings of the National Academy of Sciences of the United States of America 113 (36): 10115–10120.

Ahn D and Ho RK (2008) Tri‐phasic expression of posterior Hox genes during development of pectoral fins in zebrafish: implications for the evolution of vertebrate paired appendages. Developmental Biology 322 (1): 220–233.

Amemiya CT, Alfoldi J, Lee AP, et al. (2013) The African coelacanth genome provides insights into tetrapod evolution. Nature 496 (7445): 311–316.

Balfour FM (1881) On the development of the skeleton of the paired fins of Elasmobranchii, considered in relation to its bearings on the nature of the limbs of the vertebrata. Proceedings of the Zoological Society of London 1881: 656–671.

Berlivet S, Paquette D, Dumouchel A, et al. (2013) Clustering of tissue‐specific sub‐TADs accompanies the regulation of HoxA genes in developing limbs. PLoS Genetics 9 (12): e1004018.

Boisvert CA, Mark‐Kurik E and Ahlberg PE (2008) The pectoral fin of Panderichthys and the origin of digits. Nature 456 (7222): 636–638.

Chan YF, Marks ME, Jones FC, et al. (2010) Adaptive evolution of pelvic reduction in sticklebacks by recurrent deletion of a Pitx1 enhancer. Science 327 (5963): 302–305.

Coates MI (1993) Hox genes, fin folds and symmetry. Nature 364: 195–196.

Coates MI (1994) The origin of vertebrate limbs. Development Supplement: 169–180.

Coates MI (2003) The evolution of paired fins. Theory in Biosciences 122: 266–287.

Cohn MJ and Tickle C (1999) Developmental basis of limblessness and axial patterning in snakes. Nature 399 (6735): 474–479.

Cohn MJ, Lovejoy CO, Wolpert L and Coates MI (2002) Branching, segmentation and the metapterygial axis: pattern versus process in the vertebrate limb. Bioessays 24: 460–465.

Cole NJ, Tanaka M, Prescott A and Tickle C (2003) Expression of limb initiation genes and clues to the morphological diversification of threespine stickleback. Current Biology 13 (24): R951–R952.

Cooper KL, Sears KE, Uygur A, et al. (2014) Patterning and post‐patterning modes of evolutionary digit loss in mammals. Nature 511 (7507): 41–45.

Cresko WA, Amores A, Wilson C, et al. (2004) Parallel genetic basis for repeated evolution of armor loss in Alaskan threespine stickleback populations. Proceedings of the National Academy of Sciences of the United States of America 101 (16): 6050–6055.

Cretekos CJ, Wang Y, Green ED, et al. (2008) Regulatory divergence modifies limb length between mammals. Genes & Development 22 (2): 141–151.

Davis MC, Dahn RD and Shubin NH (2007) An autopodial‐like pattern of Hox expression in the fins of a basal actinopterygian fish. Nature 447 (7143): 473–476.

Dolle P, Izpisua‐Belmonte JC, Falkenstein H, Renucci A and Duboule D (1989) Coordinate expression of the murine Hox‐5 complex homoeobox‐containing genes during limb pattern formation. Nature 342 (6251): 767–772.

Fernandez‐Teran M, Piedra ME, Rodriguez‐Rey JC, Talamillo A and Ros MA (2003) Expression and regulation of eHAND during limb development. Developmental Dynamics 226 (4): 690–701.

Freitas R, Zhang G and Cohn MJ (2006) Evidence that mechanisms of fin development evolved in the midline of early vertebrates. Nature 442 (7106): 1033–1037.

Freitas R, Zhang G and Cohn MJ (2007) Biphasic Hoxd gene expression in shark paired fins reveals an ancient origin of the distal limb domain. PLoS One 2 (1): e754.

Funayama N, Sato Y, Matsumoto K, Ogura Y and Takahashi Y (1999) Coelom formation: binary decision of the lateral plate mesoderm is controlled by the ectoderm. Development 126: 4129–4138.

Galli A, Robay D, Osterwalder M, et al. (2010) Distinct roles of Hand2 in initiating polarity and posterior Shh expression during the onset of mouse limb bud development. PLoS Genetics 6 (4): e1000901.

Gegenbaur C (1865) Untersuchungen zur vergleichenden anatomie der wirbeltiere, vol. 2. Leipzig: Wilhelm Engelmann.

Gegenbaur C (1878) Elements of Comparative Aatomy. London: Macmilan & Co.

Gehrke AR, Schneider I, de la Calle‐Mustienes E, et al. (2015) Deep conservation of wrist and digit enhancers in fish. Proceedings of the National Academy of Sciences of the United States of America 112 (3): 803–808.

Gibson‐Brown JJ, Agulnik SI, Chapman DL, et al. (1996) Evidence of a role for T‐box genes in the evolution of limb morphogenesis and the specification of forelimb/hindlimb identity. Mechanisms of Development 56 (1–2): 93–101.

Gonzalez F, Duboule D and Spitz F (2007) Transgenic analysis of Hoxd gene regulation during digit development. Developmental Biology 306 (2): 847–859.

Hill RE, Heaney SJ and Lettice LA (2003) Sonic hedgehog: restricted expression and limb dysmorphologies. Journal of Anatomy 202 (1): 13–20.

Horton AC, Mahadevan NR, Minguillon C, et al. (2008) Conservation of linkage and evolution of developmental function within the Tbx2/3/4/5 subfamily of T‐box genes: implications for the origin of vertebrate limbs. Development Genes and Evolution 218 (11‐12): 613–628.

Jarvik E (1980) Basic Structure and Evolution of Vertebrates, vol. 2. London: Academic Press.

Johanson Z, Joss J, Boisvert CA, et al. (2007) Fish fingers: digit homologues in sarcopterygian fish fins. Journal of Experimental Zoology Part B: Molecular and Developmental Evolution 308 (6): 757–768.

Kherdjemil Y, Lalonde RL, Sheth R, et al. (2016) Evolution of Hoxa11 regulation in vertebrates is linked to the pentadactyl state. Nature 539 (7627): 89–92.

Kvon EZ, Kamneva OK, Melo US, et al. (2016) Progressive loss of function in a limb enhancer during snake evolution. Cell 167 (3): 633–642.

Leal F and Cohn MJ (2016) Loss and re‐emergence of legs in snakes by modular evolution of sonic hedgehog and HOXD enhancers. Current Biology 26 (21): 2966–2973.

Lettice LA, Horikoshi T, Heaney SJ, et al. (2002) Disruption of a long‐range cis‐acting regulator for Shh causes preaxial polydactyly. Proceedings of the National Academy of Sciences of the United States of America 99 (11): 7548–7553.

Li D, Sakuma R, Vakili NA, et al. (2014) Formation of proximal and anterior limb skeleton requires early function of Irx3 and Irx5 and is negatively regulated by Shh signaling. Developmental Cell 29 (2): 233–240.

Litingtung Y, Dahn RD, Li Y, Fallon JF and Chiang C (2002) Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature 418 (6901): 979–983.

Logan M and Tabin CJ (1999) Role of Pitx1 upstream of Tbx4 in specification of hindlimb identity. Science 283 (5408): 1736–1739.

Lopez‐Rios J, Duchesne A, Speziale D, et al. (2014) Attenuated sensing of SHH by Ptch1 underlies evolution of bovine limbs. Nature 511 (7507): 46–51.

Matsuura M, Nishihara H, Onimaru K, et al. (2008) Identification of four Engrailed genes in the Japanese lamprey, Lethenteron japonicum. Developmental Dynamics 237 (6): 1581–1589.

McGlinn E, van Bueren KL, Fiorenza S, et al. (2005) Pax9 and Jagged1 act downstream of Gli3 in vertebrate limb development. Mechanisms of Development 122 (11): 1218–1233.

Metscher BD, Takahashi K, Crow K, et al. (2005) Expression of Hoxa‐11 and Hoxa‐13 in the pectoral fin of a basal ray‐finned fish, Polyodon spathula: implications for the origin of tetrapod limbs. Evolution & Development 7 (3): 186–195.

Minguillon C, Gibson‐Brown JJ and Logan MP (2009) Tbx4/5 gene duplication and the origin of vertebrate paired appendages. Proceedings of the National Academy of Sciences of the United States of America 106 (51): 21726–21730.

Mivart SG (1879) On the fins of elasmobranchii. Transactions of the Zoological Society of London 10: 439–484.

Montavon T, Soshnikova N, Mascrez B, et al. (2011) A regulatory archipelago controls Hox genes transcription in digits. Cell 147 (5): 1132–1145.

Nelson CE, Morgan BA, Burke AC, et al. (1996) Analysis of Hox gene expression in the chick limb bud. Development 122 (5): 1449–1466.

Onimaru K, Shoguchi E, Kuratani S and Tanaka M (2011) Development and evolution of the lateral plate mesoderm: comparative analysis of amphioxus and lamprey with implications for the acquisition of paired fins. Developmental Biology 359 (1): 124–136.

Onimaru K, Kuraku S, Takagi W, et al. (2015) A shift in anterior‐posterior positional information underlies the fin‐to‐limb evolution. eLife 4: e07048.

Onimaru K, Marcon L, Musy M, Tanaka M and Sharpe J (2016) The fin‐to‐limb transition as the re‐organization of a Turing pattern. Nature Communications 7: 11582.

Orvig T (1962) Y a‐t‐il une relation directe entre les Arthrodires ptyctodontides et les Holocephales? Colloques internationaux du Centre national de la Recherche scientifique 104: 49–61.

Riddle RD, Johnson RL, Laufer E and Tabin C (1993) Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75 (7): 1401–1416.

Ruvinsky I and Gibson‐Brown JJ (2000) Genetic and developmental bases of serial homology in vertebrate limb evolution. Development 127 (24): 5233–5244.

Sagai T, Masuya H, Tamura M, et al. (2004) Phylogenetic conservation of a limb‐specific, cis‐acting regulator of Sonic hedgehog (Shh). Mammalian Genome 15 (1): 23–34.

Sagai T, Hosoya M, Mizushina Y, Tamura M and Shiroishi T (2005) Elimination of a long‐range cis‐regulatory module causes complete loss of limb‐specific Shh expression and truncation of the mouse limb. Development 132 (4): 797–803.

Sakamoto K, Onimaru K, Munakata K, et al. (2009) Heterochronic shift in Hox‐mediated activation of sonic hedgehog leads to morphological changes during fin development. PLoS One 4 (4): e5121.

Schneider I, Aneas I, Gehrke AR, et al. (2011) Appendage expression driven by the Hoxd Global Control Region is an ancient gnathostome feature. Proceedings of the National Academy of Sciences of the United States of America 108 (31): 12782–12786.

Shapiro MD, Hanken J and Rosenthal N (2003) Developmental basis of evolutionary digit loss in the Australian lizard Hemiergis. Journal of Experimental Zoology Part B: Molecular and Developmental Evolution 297 (1): 48–56.

Shapiro MD, Marks ME, Peichel CL, et al. (2004) Genetic and developmental basis of evolutionary pelvic reduction in threespine sticklebacks. Nature 428 (6984): 717–723.

Shapiro MD, Bell MA and Kingsley DM (2006) Parallel genetic origins of pelvic reduction in vertebrates. Proceedings of the National Academy of Sciences of the United States of America 103 (37): 13753–13758.

Sheth R, Marcon L, Bastida MF, et al. (2012) Hox genes regulate digit patterning by controlling the wavelength of a Turing‐type mechanism. Science 338 (6113): 1476–1480.

Sheth R, Bastida MF, Kmita M and Ros M (2014) “Self‐regulation,” a new facet of Hox genes' function. Developmental Dynamics 243 (1): 182–191.

Shubin NH and Alberch P (1986) A morphogenetic approach to the origin and basic organization of the tetrapod limb. In: Hecht MK, Wallace B and Prance GT (eds) Evolutionary Biology. New York: Plenum Press.

Shubin NH, Daeschler EB and Jenkins FA Jr (2006) The pectoral fin of Tiktaalik roseae and the origin of the tetrapod limb. Nature 440 (7085): 764–771.

Sordino P, van der Hoeven F and Duboule D (1995) Hox gene expression in teleost fins and the origin of vertebrate digits. Nature 375 (6533): 678–681.

Spitz F, Gonzalez F and Duboule D (2003) A global control region defines a chromosomal regulatory landscape containing the HoxD cluster. Cell 113 (3): 405–417.

Spitz F, Herkenne C, Morris MA and Duboule D (2005) Inversion‐induced disruption of the Hoxd cluster leads to the partition of regulatory landscapes. Nature Genetics 37 (8): 889–893.

Tabin C and Laufer E (1993) Hox genes and serial homology. Nature 361: 692–693.

Takeuchi JK, Koshiba‐Takeuchi K, Matsumoto A, et al. (1999) Tbx5 and Tbx4 genes determine the wing/leg identity of limb buds. Nature 398: 810–814.

Tamura K, Yonei‐Tamura S and Belmonte JC (1999) Differential expression of Tbx4 and Tbx5 in Zebrafish fin buds. Mechanisms of Development 87 (1‐2): 181–184.

Tanaka M, Munsterberg A, Anderson WG, et al. (2002) Fin development in a cartilaginous fish and the origin of vertebrate limbs. Nature 416 (6880): 527–531.

Tanaka M (2016) Fins into limbs: autopod acquisition and anterior elements reduction by modifying gene networks involving 5'Hox, Gli3, and Shh. Developmental Biology 413 (1): 1–7.

Tarchini B and Duboule D (2006) Control of Hoxd genes' collinearity during early limb development. Developmental Cell 10 (1): 93–103.

te Welscher P, Fernandez‐Teran M, Ros MA and Zeller R (2002) Mutual genetic antagonism involving GLI3 and dHAND prepatterns the vertebrate limb bud mesenchyme prior to SHH signaling. Genes & Development 16 (4): 421–426.

Thacher JK (1877) Median and paired fins, a contribution to the history of vertebrate limbs. Transactions of the Connecticut Academy of Arts and Sciences 3: 281–310.

Thewissen JG, Cohn MJ, Stevens LS, et al. (2006) Developmental basis for hind‐limb loss in dolphins and origin of the cetacean bodyplan. Proceedings of the National Academy of Sciences of the United States of America 103 (22): 8414–8418.

Thorogood P (1991) The development of the Teleost fin and implications for our understanding of tetrapod limb evolution. In: Hinchliffe JR, Hurle JM and Summerbell D (eds) Developmental Patterning of the Vertebrate Limb. New York: Plenum Pub Corp.

Thorogood P and Ferretti P (1993) Hox gene, fin folds and symmetry. Nature 364: 196.

Tulenko FJ, McCauley DW, Mackenzie EL, et al. (2013) Body wall development in lamprey and a new perspective on the origin of vertebrate paired fins. Proceedings of the National Academy of Sciences of the United States of America 110 (29): 11899–11904.

Vargesson N, Clarke JD, Vincent K, et al. (1997) Cell fate in the chick limb bud and relationship to gene expression. Development 124 (10): 1909–1918.

Wang B, Fallon JF and Beachy PA (2000) Hedgehog‐regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100 (4): 423–434.

Waxman JS, Keegan BR, Roberts RW, Poss KD and Yelon D (2008) Hoxb5b acts downstream of retinoic acid signaling in the forelimb field to restrict heart field potential in zebrafish. Developmental Cell 15 (6): 923–934.

Woltering JM and Duboule D (2010) The origin of digits: expression patterns versus regulatory mechanisms. Developmental Cell 18 (4): 526–532.

Woltering JM, Noordermeer D, Leleu M and Duboule D (2014) Conservation and divergence of regulatory strategies at Hox Loci and the origin of tetrapod digits. PLoS Biology 12 (1): e1001773.

Yokouchi Y, Sasaki H and Kuroiwa A (1991) Homeobox gene expression correlated with the bifurcation process of limb cartilage development. Nature 353 (6343): 443–445.

Yokoyama S, Ito Y, Ueno‐Kudoh H, et al. (2009) A systems approach reveals that the myogenesis genome network is regulated by the transcriptional repressor RP58. Developmental Cell 17 (6): 836–848.

Zakany J, Fromental‐Ramain C, Warot X and Duboule D (1997) Regulation of number and size of digits by posterior Hox genes: a dose‐dependent mechanism with potential evolutionary implications. Proceedings of the National Academy of Sciences of the United States of America 94 (25): 13695–13700.

Zakany J, Kmita M and Duboule D (2004) A dual role for Hox genes in limb anterior‐posterior asymmetry. Science 304 (5677): 1669–1672.

Zakany J, Zacchetti G and Duboule D (2007) Interactions between HOXD and Gli3 genes control the limb apical ectodermal ridge via Fgf10. Developmental Biology 306 (2): 883–893.

Zhang J, Wagh P, Guay D, et al. (2010) Loss of fish actinotrichia proteins and the fin‐to‐limb transition. Nature 466 (7303): 234–237.

Zhao X, Sirbu IO, Mic FA, et al. (2009) Retinoic acid promotes limb induction through effects on body axis extension but is unnecessary for limb patterning. Current Biology 19: 1050–1057.

Zhu M and Yu X (2009) Stem sarcopterygians have primitive polybasal fin articulation. Biology Letters 5: 372–375.

Further Reading

Tickle C (2016) Vertebrate embryo: limb development. In: Encyclopedia of Life Sciences. Chichester: John Wiley & Sons, Ltd. ISBN: 10.1002/9780470015902.a0000728.pub2.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Tanaka, Mikiko(Sep 2017) Evolution of Vertebrate Limb Development. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002099.pub2]