Limb development: A paradigm of gene regulation

Nature Reviews Genetics

Volumn 18, Issue 4, 2017, Pages 245-258

  Petit, Florence ^a,b   Sears, Karen E ^c   Ahituv, Nadav ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b University of North France   (France)

^c UNIVERSITY OF ILLINOIS AT URBANA CHAMPAIGN   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BAT; BOVINE; CELL DISRUPTION; CHROMATIN; CYTOARCHITECTURE; DNA MODIFICATION; ECTRODACTYLY; ENHANCER REGION; FINGER AMPUTATION; FORELIMB; GENE; GENE CONTROL; GENE MUTATION; GENE REARRANGEMENT; HINDLIMB; HUMAN; LIMB DEVELOPMENT; LIMB MALFORMATION; LIMB REGENERATION; NONHUMAN; PRIORITY JOURNAL; REVIEW; SNAKE; WING; ZRS GENE; ANIMAL; GENE EXPRESSION REGULATION; GENETICS; GROWTH, DEVELOPMENT AND AGING; METABOLISM; ORGANOGENESIS; SIGNAL TRANSDUCTION;

ANIMALS; FORELIMB; GENE EXPRESSION REGULATION, DEVELOPMENTAL; HINDLIMB; HUMANS; ORGANOGENESIS; SIGNAL TRANSDUCTION;

EID: 85011623248     PISSN: 14710056     EISSN: 14710064     Source Type: Journal    
DOI: 10.1038/nrg.2016.167     Document Type: Review

References (146)

1. Butterfield, N. C., McGlinn, E. & Wicking, C. The molecular regulation of vertebrate limb patterning. Curr. Top. Dev. Biol. 90, 319-341 (2010).
2. Zeller, R., Lopez-Rios, J. & Zuniga, A. Vertebrate limb bud development: moving towards integrative analysis of organogenesis. Nat. Rev. Genet. 10, 845-858 (2009).
3. Cotney, J. et al. The evolution of lineage-specific regulatory activities in the human embryonic limb. Cell 154, 185-196 (2013).
4. Eckalbar, W. L. et al. Transcriptomic and epigenomic characterization of the developing bat wing. Nat. Genet. 48, 528-536 (2016).
5. Infante, C. R., Park, S., Mihala, A. G., Kingsley, D. M. & Menke, D. B. Pitx1 broadly associates with limb enhancers and is enriched on hindlimb cis-regulatory elements. Dev. Biol. 374, 234-244 (2013).
6. Visel, A. et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854-858 (2009).
7. Vokes, S. A., Ji, H., Wong, W. H. & McMahon, A. P. A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb. Genes Dev. 22, 2651-2663 (2008).
8. Cotney, J. et al. Chromatin state signatures associated with tissue-specific gene expression and enhancer activity in the embryonic limb. Genome Res. 22, 1069-1080 (2012).
9. VanderMeer, J. E., Smith, R. P., Jones, S. L. & Ahituv, N. Genome-wide identification of signaling center enhancers in the developing limb. Development 141, 4194-4198 (2014).
10. DeMare, L. E. et al. The genomic landscape of cohesin-associated chromatin interactions. Genome Res. 23, 1224-1234 (2013).
11. Liu, H. et al. Whole transcriptome expression profiling of mouse limb tendon development by using RNA-seq. J. Orthop. Res. 33, 840-848 (2015).
12. Sears, K. E. et al. The relationship between gene network structure and expression variation among individuals and species. PLoS Genet. 11, e1005398 (2015).
13. Wang, Z. et al. Unique expression patterns of multiple key genes associated with the evolution of mammalian flight. Proc. Biol. Sci. 281, 20133133 (2014).
14. Gibson-Brown, J. J. et al. Evidence of a role for T-box genes in the evolution of limb morphogenesis and the specification of forelimb/hindlimb identity. Mech. Dev. 56, 93-101 (1996).
15. Minguillon, C., Gibson-Brown, J. J. & Logan, M. P. Tbx4/5 gene duplication and the origin of vertebrate paired appendages. Proc. Natl Acad. Sci. USA 106, 21726-21730 (2009).
16. Nishimoto, S., Wilde, S. M., Wood, S. & Logan, M. P. RA acts in a coherent feed-forward mechanism with Tbx5 to control limb bud induction and initiation. Cell Rep. 12, 879-891 (2015).
17. Agarwal, P. et al. Tbx5 is essential for forelimb bud initiation following patterning of the limb field in the mouse embryo. Development 130, 623-633 (2003).
18. Ng, J. K. et al. The limb identity gene Tbx5 promotes limb initiation by interacting with Wnt2b and Fgf10. Development 129, 5161-5170 (2002).
19. Minguillon, C., Del Buono, J. & Logan, M. P. Tbx5 and Tbx4 are not sufficient to determine limb-specific morphologies but have common roles in initiating limb outgrowth. Dev. Cell 8, 75-84 (2005).
20. Ohuchi, H. et al. The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor. Development 124, 2235-2244 (1997).
21. Sekine, K. et al. Fgf10 is essential for limb and lung formation. Nat. Genet. 21, 138-141 (1999).
22. Xu, X. et al. Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. Development 125, 753-765 (1998).
23. Rallis, C. et al. Tbx5 is required for forelimb bud formation and continued outgrowth. Development 130, 2741-2751 (2003).
24. Ahn, D. G., Kourakis, M. J., Rohde, L. A., Silver, L. M. & Ho, R. K. T-box gene tbx5 is essential for formation of the pectoral limb bud. Nature 417, 754-758 (2002).
25. Don, E. K. et al. Genetic basis of hindlimb loss in a naturally occurring vertebrate model. Biol. Open 5, 359-366 (2016).
26. Naiche, L. A. & Papaioannou, V. E. Loss of Tbx4 blocks hindlimb development and affects vascularization and fusion of the allantois. Development 130, 2681-2693 (2003).
27. Szeto, D. P., Ryan, A. K., O'Connell, S. M. & Rosenfeld, M. G. P-OTX: a PIT-1-interacting homeodomain factor expressed during anterior pituitary gland development. Proc. Natl Acad. Sci. USA 93, 7706-7710 (1996).
28. Lonfat, N. & Duboule, D. Structure, function and evolution of topologically associating domains (TADs) at HOX loci. FEBS Lett. 589, 2869-2876 (2015).
29. Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376-380 (2012).
30. Andrey, G. et al. A switch between topological domains underlies HoxD genes collinearity in mouse limbs. Science 340, 1234167 (2013).
31. Acemel, R. D. et al. A single three-dimensional chromatin compartment in amphioxus indicates a stepwise evolution of vertebrate Hox bimodal regulation. Nat. Genet. 48, 336-341 (2016).
32. Minguillon, C. et al. Hox genes regulate the onset of Tbx5 expression in the forelimb. Development 139, 3180-3188 (2012).
33. Nishimoto, S., Minguillon, C., Wood, S. & Logan, M. P. A combination of activation and repression by a colinear Hox code controls forelimb-restricted expression of Tbx5 and reveals Hox protein specificity. PLoS Genet. 10, e1004245 (2014).
34. Adachi, N., Robinson, M., Goolsbee, A. & Shubin, N. H. Regulatory evolution of Tbx5 and the origin of paired appendages. Proc. Natl Acad. Sci. USA 11 3, 10115-10120 (2016).
35. Menke, D. B., Guenther, C. & Kingsley, D. M. Dual hindlimb control elements in the Tbx4 gene and region-specific control of bone size in vertebrate limbs. Development 135, 2543-2553 (2008).
36. Infante, C. R. et al. Shared enhancer activity in the limbs and phallus and functional divergence of a limb-genital cis-regulatory element in snakes. Dev. Cell 35, 107-119 (2015).
37. Chan, Y. F. et al. Adaptive evolution of pelvic reduction in sticklebacks by recurrent deletion of a Pitx1 enhancer. Science 327, 302-305 (2010).
38. Rodriguez-Esteban, C. et al. The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity. Nature 398, 814-818 (1999).
39. Takeuchi, J. K. et al. Tbx5 and Tbx4 genes determine the wing/leg identity of limb buds. Nature 398, 810-814 (1999).
40. Logan, M. & Tabin, C. J. Role of Pitx1 upstream of Tbx4 in specification of hindlimb identity. Science 283, 1736-1739 (1999).
41. DeLaurier, A., Schweitzer, R. & Logan, M. Pitx1 determines the morphology of muscle, tendon, and bones of the hindlimb. Dev. Biol. 299, 22-34 (2006).
42. Ouimette, J. F., Jolin, M. L., L'Honore, A., Gifuni, A. & Drouin, J. Divergent transcriptional activities determine limb identity. Nat. Commun. 1, 35 (2010).
43. Lanctot, C., Moreau, A., Chamberland, M., Tremblay, M. L. & Drouin, J. Hindlimb patterning and mandible development require the Ptx1 gene. Development 126, 1805-1810 (1999).
44. Szeto, D. P. et al. Role of the Bicoid-related homeodomain factor Pitx1 in specifying hindlimb morphogenesis and pituitary development. Genes Dev. 13, 484-494 (1999).
45. Duboc, V. & Logan, M. P. Pitx1 is necessary for normal initiation of hindlimb outgrowth through regulation of Tbx4 expression and shapes hindlimb morphologies via targeted growth control. Development 138, 5301-5309 (2011).
46. Al-Qattan, M. M., Al-Thunayan, A., Alabdulkareem, I. & Al Balwi, M. Liebenberg syndrome is caused by a deletion upstream to the PITX1 gene resulting in transformation of the upper limbs to reflect lower limb characteristics. Gene 524, 65-71 (2013).
47. Spielmann, M. et al. Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus. Am. J. Hum. Genet. 91, 629-635 (2012).
48. Seoighe, D. M. et al. A chromosomal 5q31.1 gain involving PITX1 causes Liebenberg syndrome. Am. J. Med. Genet. A 164A, 2958-2960 (2014).
49. Domyan, E. T. et al. Molecular shifts in limb identity underlie development of feathered feet in two domestic avian species. eLife 5, e12115 (2016).
50. Sears, K. E., Behringer, R. R., Rasweiler, J. J. IV & Niswander, L. A. Development of bat flight: morphologic and molecular evolution of bat wing digits. Proc. Natl Acad. Sci. USA 103, 6581-6586 (2006).
51. Booker, B. M. et al. Bat accelerated regions identify a bat forelimb specific enhancer in the HoxD locus. PLoS Genet. 12, e1005738 (2016).
52. Hockman, D. et al. A second wave of Sonic hedgehog expression during the development of the bat limb. Proc. Natl Acad. Sci. USA 105, 16982-16987 (2008).
53. Cretekos, C. J. et al. Regulatory divergence modifies limb length between mammals. Genes Dev. 22, 141-151 (2008).
54. Cretekos, C. J. et al. Isolation, genomic structure and developmental expression of Fgf8 in the short-tailed fruit bat, Carollia perspicillata. Int. J. Dev. Biol. 51, 333-338 (2007).
55. Chen, C. H., Cretekos, C. J., Rasweiler, J. J. IV & Behringer, R. R. Hoxd13 expression in the developing limbs of the short-tailed fruit bat, Carollia perspicillata. Evol. Dev. 7, 130-141 (2005).
56. Cooper, K. L. et al. Patterning and post-patterning modes of evolutionary digit loss in mammals. Nature 5 11, 41-45 (2014).
57. Sears, K. E. et al. Developmental basis of mammalian digit reduction: a case study in pigs. Evol. Dev. 13, 533-541 (2011).
58. Cooper, K. L. et al. Multiple phases of chondrocyte enlargement underlie differences in skeletal proportions. Nature 495, 375-378 (2013).
59. Lopez-Rios, J. et al. Attenuated sensing of SHH by Ptch1 underlies evolution of bovine limbs. Nature 5 11, 46-51 (2014).
60. Thewissen, J. G. M. et al. Developmental basis for hind-limb loss in dolphins and origin of the cetacean bodyplan. Proc. Natl Acad. Sci. USA 103, 8414-8418 (2006).
61. Keyte, A. L. & Smith, K. K. Developmental origins of precocial forelimbs in marsupial neonates. Development 137, 4283-4294 (2010).
62. Sears, K. E. et al. Disparate Igf1 expression and growth in the fore-and hind limbs of a marsupial (Monodelphis domestica). J. Exp. Zool. B Mol. Dev. Evol. 318, 279-293 (2012).
63. Chew, K. Y., Yu, H., Pask, A. J., Shaw, G. & Renfree, M. B. HOXA13 and HOXD13 expression during development of the syndactylous digits in the marsupial Macropus eugenii. BMC Dev. Biol. 12, 2 (2012).
64. Sanger, T. J., Revell, L. J., Gibson-Brown, J. J. & Losos, J. B. Repeated modification of early limb morphogenesis programmes underlies the convergence of relative limb length in Anolis lizards. Proc. Biol. Sci. 279, 739-748 (2012).
65. Cohn, M. J. & Tickle, C. Developmental basis of limblessness and axial patterning in snakes. Nature 399, 474-479 (1999).
66. Shapiro, M. D., Hanken, J. & Rosenthal, N. Developmental basis of evolutionary digit loss in the Australian lizard Hemiergis. J. Exp. Zool. B Mol. Dev. Evol. 297, 48-56 (2003).
67. Leal, F. & Cohn, M. J. Loss and re-emergence of legs in snakes by modular evolution of Sonic hedgehog and HOXD enhancers. Curr. Biol. 26, 2966-2973 (2016).
68. Kvon, E. Z. et al. Progressive loss of function in a limb enhancer during snake evolution. Cell. 167, 633-642 (2016).
69. Guerreiro, I. et al. Reorganisation of Hoxd regulatory landscapes during the evolution of a snake-like body plan. eLife 5, e16087 (2016).
70. Butterfield, N. C. et al. Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb. Development 136, 3515-3524 (2009).
71. Dai, M. et al. Differential expression of Meis2, Mab21l2 and Tbx3 during limb development associated with diversification of limb morphology in mammals. PLoS ONE 9, e106100 (2014).
72. Sugiura, T., Wang, H., Barsacchi, R., Simon, A. & Tanaka, E. M. MARCKS-like protein is an initiating molecule in axolotl appendage regeneration. Nature 531, 237-240 (2016).
73. Endo, T., Bryant, S. V. & Gardiner, D. M. A stepwise model system for limb regeneration. Dev. Biol. 270, 135-145 (2004).
74. Nacu, E., Gromberg, E., Oliveira, C. R., Drechsel, D. & Tanaka, E. M. FGF8 and SHH substitute for anterior-posterior tissue interactions to induce limb regeneration. Nature 533, 407-410 (2016).
75. Muneoka, K., Holler-Dinsmore, G. & Bryant, S. Regeneration from discontinuous circumferences in axolotl limbs. Prog. Clin. Biol. Res. 217A, 61-65 (1986).
76. Yakushiji, N. et al. Correlation between Shh expression and DNA methylation status of the limb-specific Shh enhancer region during limb regeneration in amphibians. Dev. Biol. 312, 171-182 (2007).
77. Hayashi, S. et al. Epigenetic modification maintains intrinsic limb-cell identity in Xenopus limb bud regeneration. Dev. Biol. 406, 271-282 (2015).
78. Kang, J. et al. Modulation of tissue repair by regeneration enhancer elements. Nature 532, 201-206 (2016).
79. VanderMeer, J. E. & Ahituv, N. Cis-regulatory mutations are a genetic cause of human limb malformations. Dev. Dyn. 240, 920-930 (2011).
80. Spielmann, M. & Mundlos, S. Looking beyond the genes: the role of non-coding variants in human disease. Hum. Mol. Genet. 25, R157-R165 (2016).
81. Lettice, L. A. et al. Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proc. Natl Acad. Sci. USA 99, 7548-7553 (2002).
82. Williamson, I., Lettice, L. A., Hill, R. E. & Bickmore, W. A. Shh and ZRS enhancer colocalisation is specific to the zone of polarising activity. Development 143, 2994-3001 (2016).
83. Amano, T. et al. Chromosomal dynamics at the Shh locus: limb bud-specific differential regulation of competence and active transcription. Dev. Cell 16, 47-57 (2009).
84. Lettice, L. A. et al. Development of five digits is controlled by a bipartite long-range cis-regulator. Development 141, 1715-1725 (2014).
85. Galli, A. et al. Distinct roles of Hand2 in initiating polarity and posterior Shh expression during the onset of mouse limb bud development. PLoS Genet. 6, e1000901 (2010).
86. Capellini, T. D. et al. Pbx1/Pbx2 requirement for distal limb patterning is mediated by the hierarchical control of Hox gene spatial distribution and Shh expression. Development 133, 2263-2273 (2006).
87. Lettice, L. A. et al. Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly. Dev. Cell 22, 459-467 (2012).
88. Kozhemyakina, E., Ionescu, A. & Lassar, A. B. GATA6 is a crucial regulator of Shh in the limb bud. PLoS Genet. 10, e1004072 (2014).
89. Harfe, B. D. et al. Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell 11 8, 517-528 (2004).
90. Riddle, R. D., Johnson, R. L., Laufer, E. & Tabin, C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75, 1401-1416 (1993).
91. Sagai, T., Hosoya, M., Mizushina, Y., Tamura, M. & Shiroishi, T. Elimination of a long-range cis-regulatory module causes complete loss of limb-specific Shh expression and truncation of the mouse limb. Development 132, 797-803 (2005).
92. Sharpe, J. et al. Identification of sonic hedgehog as a candidate gene responsible for the polydactylous mouse mutant Sasquatch. Curr. Biol. 9, 97-100 (1999).
93. Lettice, L. A., Hill, A. E., Devenney, P. S. & Hill, R. E. Point mutations in a distant sonic hedgehog cis-regulator generate a variable regulatory output responsible for preaxial polydactyly. Hum. Mol. Genet. 17, 978-985 (2008).
94. Dorshorst, B., Okimoto, R. & Ashwell, C. Genomic regions associated with dermal hyperpigmentation, polydactyly and other morphological traits in the Silkie chicken. J. Hered. 101, 339-350 (2010).
95. Shamseldin, H. E., Faden, M. A., Alashram, W. & Alkuraya, F. S. Identification of a novel DLX5 mutation in a family with autosomal recessive split hand and foot malformation. J. Med. Genet. 49, 16-20 (2012).
96. Sowinska-Seidler, A., Badura-Stronka, M., Latos-Bielenska, A., Stronka, M. & Jamsheer, A. Heterozygous DLX5 nonsense mutation associated with isolated split-hand/foot malformation with reduced penetrance and variable expressivity in two unrelated families. Birth Defects Res. A Clin. Mol. Teratol. 100, 764-771 (2014).
97. Wang, X. et al. Exome sequencing reveals a heterozygous DLX5 mutation in a Chinese family with autosomal-dominant split-hand/foot malformation. Eur. J. Hum. Genet. 22, 1105-1110 (2014).
98. Ullah, A., Ullah, M. F., Khalid, Z. M. & Ahmad, W. A novel heterozygous frameshift mutation in DLX5 gene underlies isolated split hand foot malformation type 1. Pediatr. Int. 58, 1348-1350 (2016).
99. Birnbaum, R. Y. et al. Functional characterization of tissue-specific enhancers in the DLX5/6 locus. Hum. Mol. Genet. 21, 4930-4938 (2012).
100. Rasmussen, M. B. et al. Phenotypic subregions within the split-hand/foot malformation 1 locus. Hum. Genet. 135, 345-357 (2016).
101. Birnbaum, R. Y. et al. Coding exons function as tissue-specific enhancers of nearby genes. Genome Res. 22, 1059-1068 (2012).
102. Marinic, M., Aktas, T., Ruf, S. & Spitz, F. An integrated holo-enhancer unit defines tissue and gene specificity of the Fgf8 regulatory landscape. Dev. Cell 24, 530-542 (2013).
103. Sheth, R. et al. Decoupling the function of Hox and Shh in developing limb reveals multiple inputs of Hox genes on limb growth. Development 140, 2130-2138 (2013).
104. Goodman, F. R., Majewski, F., Collins, A. L. & Scambler, P. J. A 117-kb microdeletion removing HOXD9-HOXD13 and EVX2 causes synpolydactyly. Am. J. Hum. Genet. 70, 547-555 (2002).
105. Spitz, F., Gonzalez, F. & Duboule, D. A global control region defines a chromosomal regulatory landscape containing the HoxD cluster. Cell 11 3, 405-417 (2003).
106. Klopocki, E. et al. Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion. J. Med. Genet. 49, 119-125 (2012).
107. Schatz, O., Langer, E. & Ben-Arie, N. Gene dosage of the transcription factor Fingerin (bHLHA9) affects digit development and links syndactyly to ectrodactyly. Hum. Mol. Genet. 23, 5394-5401 (2014).
108. Malik, S. et al. Mutations affecting the BHLHA9 DNA-binding domain cause MSSD, mesoaxial synostotic syndactyly with phalangeal reduction, Malik-Percin type. Am. J. Hum. Genet. 95, 649-659 (2014).
109. Lettice, L. A. et al. Enhancer-adoption as a mechanism of human developmental disease. Hum. Mutat. 32, 1492-1499 (2011).
110. Matharu, N. & Ahituv, N. Minor loops in major folds: enhancer-promoter looping, chromatin restructuring, and their association with transcriptional regulation and disease. PLoS Genet. 11, e1005640 (2015).
111. Lupianez, D. G. et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 161, 1012-1025 (2015).
112. Franke, M. et al. Formation of new chromatin domains determines pathogenicity of genomic duplications. Nature 538, 265-269 (2016).
113. Inoue, F. & Ahituv, N. Decoding enhancers using massively parallel reporter assays. Genomics 106, 159-164 (2015).
114. Shalem, O., Sanjana, N. E. & Zhang, F. High-throughput functional genomics using CRISPR-Cas9. Nat. Rev. Genet. 16, 299-311 (2015).
115. Ritter, D. I., Dong, Z., Guo, S. & Chuang, J. H. Transcriptional enhancers in protein-coding exons of vertebrate developmental genes. PLoS ONE 7, e35202 (2012).
116. Zhou, V. W., Goren, A. & Bernstein, B. E. Charting histone modifications and the functional organization of mammalian genomes. Nat. Rev. Genet. 12, 7-18 (2011).
117. Koch, F. et al. Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters. Nat. Struct. Mol. Biol. 18, 956-963 (2011).
118. van Arensbergen, J., van Steensel, B. & Bussemaker, H. J. In search of the determinants of enhancer-promoter interaction specificity. Trends Cell Biol. 24, 695-702 (2014).
119. Merika, M., Williams, A. J., Chen, G., Collins, T. & Thanos, D. Recruitment of CBP/p300 by the IFNβ enhanceosome is required for synergistic activation of transcription. Mol. Cell 1, 277-287 (1998).
120. Lai, F. et al. Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature 494, 497-501 (2013).
121. Boisvert, C. A., Mark-Kurik, E. & Ahlberg, P. E. The pectoral fin of Panderichthys and the origin of digits. Nature 456, 636-638 (2008).
122. Sordino, P., van der Hoeven, F. & Duboule, D. Hox gene expression in teleost fins and the origin of vertebrate digits. Nature 375, 678-681 (1995).
123. Spitz, F., Gonzales, F. & Duboule, D. A global control region defines a chromosomal regulatory landscape containing the HoxD cluster. Cell 11 3, 405-417 (2003).
124. Shubin, N., Tabin, C. & Carroll, S. Fossils, genes and the evolution of animal limbs. Nature 388, 639-648 (1997).
125. Dolle, P. et al. Disruption of the Hoxd13 gene induces localized heterochrony leading to mice with neotenic limbs. Cell 75, 431-441 (1993).
126. Kherdjemil, Y. et al. Evolution of Hoxa11 regulation in vertebrates is linked to the pentadactyl state. Nature 539, 89-92 (2016).
127. Freitas, R., Zhang, G. & Cohn, M. J. Biphasic Hoxd gene expression in shark paired fins reveals an ancient origin of the distal limb domain. PLoS ONE 2, e754 (2007).
128. Woltering, J. M., Noordermeer, D., Leleu, M. & Duboule, D. Conservation and divergence of regulatory strategies at Hox loci and the origin of tetrapod digits. PLoS Biol. 12, e1001773 (2014).
129. Schneider, I. & Shubin, N. H. The origin of the tetrapod limb: from expeditions to enhancers. Trends Genet. 29, 419-426 (2013).
130. Davis, M. C., Dahn, R. D. & Shubin, N. H. An autopodial-like pattern of Hox expression in the fins of a basal actinopterygian fish. Nature 447, 473-476 (2007).
131. Shubin, N. H., Daeschler, E. B. & Jenkins, F. A. Jr. The pectoral fin of Tiktaalik roseae and the origin of the tetrapod limb. Nature 440, 764-771 (2006).
132. Gehrke, A. R. et al. Deep conservation of wrist and digit enhancers in fish. Proc. Natl Acad. Sci. USA 11 2, 803-808 (2015).
133. Johanson, Z. et al. Fish fingers: digit homologues in sarcopterygian fish fins. J. Exp. Zool. B Mol. Dev. Evol. 308B, 757-768 (2007).
134. Ahn, D. & Ho, R. K. Tri-phasic expression of posterior Hox genes during development of pectoral fins in zebrafish: implications for the evolution of vertebrate paired appendages. Dev. Biol. 322, 220-233 (2008).
135. Nakamura, T., Gehrke, A. R., Lemberg, J., Szymaszek, J. & Shubin, N. H. Digits and fin rays share common developmental histories. Nature 537, 225-228 (2016).
136. Schneider, I. et al. Appendage expression driven by the Hoxd Global Control Region is an ancient gnathostome feature. Proc. Natl Acad. Sci. USA 108, 12782-12786 (2011).
137. Kawakami, Y. et al. WNT signals control FGF-dependent limb initiation and AER induction in the chick embryo. Cell 104, 891-900 (2001).
138. Kengaku, M. et al. Distinct WNT pathways regulating AER formation and dorsoventral polarity in the chick limb bud. Science 280, 1274-1277 (1998).
139. Yang, A. et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714-718 (1999).
140. Ianakiev, P. et al. Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27. Am. J. Hum. Genet. 67, 59-66 (2000).
141. Robledo, R. F., Rajan, L., Li, X. & Lufkin, T. The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development. Genes Dev. 16, 1089-1101 (2002).
142. Lo Iacono, N. et al. Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects. Development 135, 1377-1388 (2008).
143. Kouwenhoven, E. N. et al. Genome-wide profiling of p63 DNA-binding sites identifies an element that regulates gene expression during limb development in the 7q21 SHFM1 locus. PLoS Genet. 6, e1001065 (2010).
144. Guerrini, L., Costanzo, A. & Merlo, G. R. A symphony of regulations centered on p63 to control development of ectoderm-derived structures. J. Biomed. Biotechnol. 2011, 864904 (2011).
145. Haro, E. et al. Sp6 and Sp8 transcription factors control AER formation and dorsal-ventral patterning in limb development. PLoS Genet. 10, e1004468 (2014).
146. Lango Allen, H. et al. Next generation sequencing of chromosomal rearrangements in patients with split-hand/split-foot malformation provides evidence for DYNC1I1 exonic enhancers of DLX5/6 expression in humans. J. Med. Genet. 51, 264-267 (2014).