Limb development: a paradigm of gene regulation (original) (raw)

• Butterfield, N. C., McGlinn, E. & Wicking, C. The molecular regulation of vertebrate limb patterning. Curr. Top. Dev. Biol. 90, 319–341 (2010).
  CAS PubMed Google Scholar
• Zeller, R., Lopez-Rios, J. & Zuniga, A. Vertebrate limb bud development: moving towards integrative analysis of organogenesis. Nat. Rev. Genet. 10, 845–858 (2009).
  CAS PubMed Google Scholar
• Cotney, J. et al. The evolution of lineage-specific regulatory activities in the human embryonic limb. Cell 154, 185–196 (2013).
  CAS PubMed Central PubMed Google Scholar
• Eckalbar, W. L. et al. Transcriptomic and epigenomic characterization of the developing bat wing. Nat. Genet. 48, 528–536 (2016). By comparing RNA-seq and ChIP–seq analyses in the developing bat forelimb and hindlimb, this study identifies regions in the bat genome that are differentially modified and could contribute to bat wing development.
  CAS PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Visel, A. et al. ChIP–seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854–858 (2009).
  CAS PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• 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). Using H3K27ac ChIP–seq in the AER and ZPA signalling centres of the limb bud, this study identifies novel enhancers that could be important regulators of genes involved in tetrapod limb patterning.
  CAS PubMed Central PubMed Google Scholar
• DeMare, L. E. et al. The genomic landscape of cohesin-associated chromatin interactions. Genome Res. 23, 1224–1234 (2013). This genome-wide scale analysis of cohesin-associated interactions in the developing mouse limb provides insights into the regulatory architecture of limb development.
  CAS PubMed Central PubMed Google Scholar
• Liu, H. et al. Whole transcriptome expression profiling of mouse limb tendon development by using RNA-seq. J. Orthop. Res. 33, 840–848 (2015).
  PubMed Central PubMed Google Scholar
• Sears, K. E. et al. The relationship between gene network structure and expression variation among individuals and species. PLoS Genet. 11, e1005398 (2015).
  PubMed Central PubMed Google Scholar
• Wang, Z. et al. Unique expression patterns of multiple key genes associated with the evolution of mammalian flight. Proc. Biol. Sci. 281, 20133133 (2014).
  PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Ng, J. K. et al. The limb identity gene Tbx5 promotes limb initiation by interacting with Wnt2b and Fgf10. Development 129, 5161–5170 (2002).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Sekine, K. et al. Fgf10 is essential for limb and lung formation. Nat. Genet. 21, 138–141 (1999).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Rallis, C. et al. Tbx5 is required for forelimb bud formation and continued outgrowth. Development 130, 2741–2751 (2003).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Don, E. K. et al. Genetic basis of hindlimb loss in a naturally occurring vertebrate model. Biol. Open 5, 359–366 (2016).
  CAS PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Lonfat, N. & Duboule, D. Structure, function and evolution of topologically associating domains (TADs) at HOX loci. FEBS Lett. 589, 2869–2876 (2015).
  CAS PubMed Google Scholar
• Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012). This study uses Hi-C to determine the topological domains of the human and mouse genomes in embryonic stem cells and terminally differentiated cells, providing major insights into the 3D spatial organization of mammalian genomes.
  CAS PubMed Central PubMed Google Scholar
• Andrey, G. et al. A switch between topological domains underlies HoxD genes collinearity in mouse limbs. Science 340, 1234167 (2013).
  PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Minguillon, C. et al. Hox genes regulate the onset of Tbx5 expression in the forelimb. Development 139, 3180–3188 (2012).
  CAS PubMed Central PubMed Google Scholar
• 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).
  PubMed Central PubMed Google Scholar
• Adachi, N., Robinson, M., Goolsbee, A. & Shubin, N. H. Regulatory evolution of Tbx5 and the origin of paired appendages. Proc. Natl Acad. Sci. USA 113, 10115–10120 (2016).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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). This paper shows that numerous limb enhancers are retained in snake genomes, and functional enhancer assays show how their function could have changed.
  CAS PubMed Central PubMed Google Scholar
• Chan, Y. F. et al. Adaptive evolution of pelvic reduction in sticklebacks by recurrent deletion of a Pitx1 enhancer. Science 327, 302–305 (2010).
  CAS PubMed Google Scholar
• Rodriguez-Esteban, C. et al. The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity. Nature 398, 814–818 (1999).
  CAS PubMed Google Scholar
• Takeuchi, J. K. et al. Tbx5 and Tbx4 genes determine the wing/leg identity of limb buds. Nature 398, 810–814 (1999).
  CAS PubMed Google Scholar
• Logan, M. & Tabin, C. J. Role of Pitx1 upstream of Tbx4 in specification of hindlimb identity. Science 283, 1736–1739 (1999).
  CAS PubMed Google Scholar
• DeLaurier, A., Schweitzer, R. & Logan, M. Pitx1 determines the morphology of muscle, tendon, and bones of the hindlimb. Dev. Biol. 299, 22–34 (2006).
  CAS PubMed Google Scholar
• Ouimette, J. F., Jolin, M. L., L'Honore, A., Gifuni, A. & Drouin, J. Divergent transcriptional activities determine limb identity. Nat. Commun. 1, 35 (2010).
  PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• Seoighe, D. M. et al. A chromosomal 5q31.1 gain involving PITX1 causes Liebenberg syndrome. Am. J. Med. Genet. A 164A, 2958–2960 (2014).
  PubMed Google Scholar
• Domyan, E. T. et al. Molecular shifts in limb identity underlie development of feathered feet in two domestic avian species. eLife 5, e12115 (2016).
  PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Booker, B. M. et al. Bat accelerated regions identify a bat forelimb specific enhancer in the HoxD locus. PLoS Genet. 12, e1005738 (2016).
  PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Cretekos, C. J. et al. Regulatory divergence modifies limb length between mammals. Genes Dev. 22, 141–151 (2008). By replacing a mouse limb enhancer sequence with a bat sequence, this article shows how changes in regulatory elements can have a functional consequence.
  CAS PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Cooper, K. L. et al. Patterning and post-patterning modes of evolutionary digit loss in mammals. Nature 511, 41–45 (2014).
  CAS PubMed Central PubMed Google Scholar
• Sears, K. E. et al. Developmental basis of mammalian digit reduction: a case study in pigs. Evol. Dev. 13, 533–541 (2011).
  PubMed Google Scholar
• Cooper, K. L. et al. Multiple phases of chondrocyte enlargement underlie differences in skeletal proportions. Nature 495, 375–378 (2013).
  CAS PubMed Central PubMed Google Scholar
• Lopez-Rios, J. et al. Attenuated sensing of SHH by Ptch1 underlies evolution of bovine limbs. Nature 511, 46–51 (2014). This article shows that digit reduction in cattle is associated with changes in SHH signalling that are due to evolutionary alterations of a PTCH1 regulatory module.
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Keyte, A. L. & Smith, K. K. Developmental origins of precocial forelimbs in marsupial neonates. Development 137, 4283–4294 (2010).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• 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).
  PubMed Google Scholar
• Cohn, M. J. & Tickle, C. Developmental basis of limblessness and axial patterning in snakes. Nature 399, 474–479 (1999).
  CAS PubMed Google Scholar
• 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).
  PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Kvon, E. Z. et al. Progressive loss of function in a limb enhancer during snake evolution. Cell. 167, 633–642 (2016).
  CAS PubMed Central PubMed Google Scholar
• Guerreiro, I. et al. Reorganisation of Hoxd regulatory landscapes during the evolution of a snake-like body plan. eLife 5, e16087 (2016).
  PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• Endo, T., Bryant, S. V. & Gardiner, D. M. A stepwise model system for limb regeneration. Dev. Biol. 270, 135–145 (2004).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Muneoka, K., Holler-Dinsmore, G. & Bryant, S. Regeneration from discontinuous circumferences in axolotl limbs. Prog. Clin. Biol. Res. 217A, 61–65 (1986).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Hayashi, S. et al. Epigenetic modification maintains intrinsic limb-cell identity in Xenopus limb bud regeneration. Dev. Biol. 406, 271–282 (2015).
  CAS PubMed Google Scholar
• Kang, J. et al. Modulation of tissue repair by regeneration enhancer elements. Nature 532, 201–206 (2016). Using epigenetic profiling in the regenerating hearts and fins of zebrafish, this study provides evidence for TREEs that trigger gene expression in injury sites.
  CAS PubMed Central PubMed Google Scholar
• VanderMeer, J. E. & Ahituv, N. _Cis_-regulatory mutations are a genetic cause of human limb malformations. Dev. Dyn. 240, 920–930 (2011).
  CAS PubMed Central PubMed Google Scholar
• Spielmann, M. & Mundlos, S. Looking beyond the genes: the role of non-coding variants in human disease. Hum. Mol. Genet. 25, R157–R165 (2016).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Lettice, L. A. et al. Development of five digits is controlled by a bipartite long-range _cis_-regulator. Development 141, 1715–1725 (2014).
  CAS PubMed Central PubMed Google Scholar
• 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).
  PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• Kozhemyakina, E., Ionescu, A. & Lassar, A. B. GATA6 is a crucial regulator of Shh in the limb bud. PLoS Genet. 10, e1004072 (2014).
  PubMed Central PubMed Google Scholar
• Harfe, B. D. et al. Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell 118, 517–528 (2004).
  CAS PubMed Google Scholar
• Riddle, R. D., Johnson, R. L., Laufer, E. & Tabin, C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75, 1401–1416 (1993).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Birnbaum, R. Y. et al. Functional characterization of tissue-specific enhancers in the DLX5/6 locus. Hum. Mol. Genet. 21, 4930–4938 (2012).
  CAS PubMed Central PubMed Google Scholar
• Rasmussen, M. B. et al. Phenotypic subregions within the split-hand/foot malformation 1 locus. Hum. Genet. 135, 345–357 (2016).
  PubMed Google Scholar
• Birnbaum, R. Y. et al. Coding exons function as tissue-specific enhancers of nearby genes. Genome Res. 22, 1059–1068 (2012).
  CAS PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• Spitz, F., Gonzalez, F. & Duboule, D. A global control region defines a chromosomal regulatory landscape containing the HoxD cluster. Cell 113, 405–417 (2003).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• Lettice, L. A. et al. Enhancer-adoption as a mechanism of human developmental disease. Hum. Mutat. 32, 1492–1499 (2011).
  CAS PubMed Google Scholar
• 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).
  PubMed Central PubMed Google Scholar
• Lupianez, D. G. et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 161, 1012–1025 (2015). This article describes distinct human limb malformations caused by chromosomal rearrangements that disrupt TAD boundaries, providing criteria for predicting the pathogenicity of structural variants, particularly in non-coding regions of the genome.
  CAS PubMed Central PubMed Google Scholar
• Franke, M. et al. Formation of new chromatin domains determines pathogenicity of genomic duplications. Nature 538, 265–269 (2016).
  CAS PubMed Google Scholar
• Inoue, F. & Ahituv, N. Decoding enhancers using massively parallel reporter assays. Genomics 106, 159–164 (2015).
  CAS PubMed Google Scholar
• Shalem, O., Sanjana, N. E. & Zhang, F. High-throughput functional genomics using CRISPR–Cas9. Nat. Rev. Genet. 16, 299–311 (2015).
  CAS PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• 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).
  PubMed Google Scholar
• Koch, F. et al. Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters. Nat. Struct. Mol. Biol. 18, 956–963 (2011).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Lai, F. et al. Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature 494, 497–501 (2013).
  CAS PubMed Central PubMed Google Scholar
• Boisvert, C. A., Mark-Kurik, E. & Ahlberg, P. E. The pectoral fin of Panderichthys and the origin of digits. Nature 456, 636–638 (2008).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Spitz, F., Gonzales, F. & Duboule, D. A global control region defines a chromosomal regulatory landscape containing the HoxD cluster. Cell 113, 405–417 (2003).
  CAS PubMed Google Scholar
• Shubin, N., Tabin, C. & Carroll, S. Fossils, genes and the evolution of animal limbs. Nature 388, 639–648 (1997).
  CAS PubMed Google Scholar
• Dolle, P. et al. Disruption of the Hoxd13 gene induces localized heterochrony leading to mice with neotenic limbs. Cell 75, 431–441 (1993).
  CAS PubMed Google Scholar
• Kherdjemil, Y. et al. Evolution of Hoxa11 regulation in vertebrates is linked to the pentadactyl state. Nature 539, 89–92 (2016).
  CAS PubMed Central PubMed Google Scholar
• 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).
  PubMed Central PubMed Google Scholar
• 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).
  PubMed Central PubMed Google Scholar
• Schneider, I. & Shubin, N. H. The origin of the tetrapod limb: from expeditions to enhancers. Trends Genet. 29, 419–426 (2013).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Gehrke, A. R. et al. Deep conservation of wrist and digit enhancers in fish. Proc. Natl Acad. Sci. USA 112, 803–808 (2015).
  CAS PubMed Google Scholar
• Johanson, Z. et al. Fish fingers: digit homologues in sarcopterygian fish fins. J. Exp. Zool. B Mol. Dev. Evol. 308B, 757–768 (2007).
  Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Kawakami, Y. et al. WNT signals control FGF-dependent limb initiation and AER induction in the chick embryo. Cell 104, 891–900 (2001).
  CAS PubMed Google Scholar
• Kengaku, M. et al. Distinct WNT pathways regulating AER formation and dorsoventral polarity in the chick limb bud. Science 280, 1274–1277 (1998).
  CAS PubMed Google Scholar
• Yang, A. et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714–718 (1999).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Central PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  PubMed Central PubMed Google Scholar
• 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).
  PubMed Central PubMed Google Scholar
• Haro, E. et al. Sp6 and Sp8 transcription factors control AER formation and dorsal-ventral patterning in limb development. PLoS Genet. 10, e1004468 (2014).
  PubMed Central PubMed Google Scholar
• 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).
  PubMed Google Scholar