Vertebrate limb bud development: moving towards integrative analysis of organogenesis (original) (raw)
Fernandez-Teran, M. & Ros, M. A. The apical ectodermal ridge: morphological aspects and signaling pathways. Int. J. Dev. Biol.52, 857–871 (2008). ArticlePubMed Google Scholar
King, M., Arnold, J. S., Shanske, A. & Morrow, B. E. T-genes and limb bud development. Am. J. Med. Genet. A140, 1407–1413 (2006). ArticlePubMedCAS Google Scholar
Zakany, J. & Duboule, D. The role of Hox genes during vertebrate limb development. Curr. Opin. Genet. Dev.17, 359–366 (2007). ArticleCASPubMed Google Scholar
Shubin, N., Tabin, C. & Carroll, S. Deep homology and the origins of evolutionary novelty. Nature457, 818–823 (2009). ArticleCASPubMed Google Scholar
Saunders, J. W. The proximo-distal sequence of origin of limb parts of the chick wing and the role of the ectoderm. J. Exp. Zool.108, 363–404 (1948). ArticlePubMed Google Scholar
Summerbell, D., Lewis, J. H. & Wolpert, L. Positional information in chick limb morphogenesis. Nature244, 492–496 (1973). ArticleCASPubMed Google Scholar
Niswander, L., Tickle, C., Vogel, A., Booth, I. & Martin, G. R. FGF-4 replaces the apical ectodermal ridge and directs outgrowth and patterning of the limb. Cell75, 579–587 (1993). ArticleCASPubMed Google Scholar
Lewandoski, M., Sun, X. & Martin, G. R. Fgf8 signalling from the AER is essential for normal limb development. Nature Genet.26, 460–463 (2000). ArticleCASPubMed Google Scholar
Mariani, F. V., Ahn, C. P. & Martin, G. R. Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning. Nature453, 401–405 (2008). An in-depth genetic analysis of four FGFs during mouse limb bud development that shows the contribution of each to AER signalling. AER-FGFs promote cell proliferation and regulate PD limb axis patterning. ArticleCASPubMedPubMed Central Google Scholar
Fallon, J. F. et al. FGF-2: apical ectodermal ridge growth factor for chick limb development. Science264, 104–107 (1994). ArticleCASPubMed Google Scholar
Cohn, M. J., Izpisúa-Belmonte, J. C., Abud, H., Heath, J. K. & Tickle, C. Fibroblast growth factors induce additional limb development from the flank of chick embryos. Cell80, 739–746 (1995). ArticleCASPubMed Google Scholar
Kawakami, Y. et al. WNT signals control FGF-dependent limb initiation and AER induction in the chick embryo. Cell104, 891–900 (2001). ArticleCASPubMed Google Scholar
Agarwal, P. et al. Tbx5 is essential for forelimb bud initiation following patterning of the limb field in the mouse embryo. Development130, 623–633 (2003). ArticleCASPubMed Google Scholar
Benazet, J. D. et al. A self-regulatory system of interlinked signaling feedback loops controls mouse limb patterning. Science323, 1050–1053 (2009). In this study, mouse genetic models and mathematical modelling reveal the self-regulatory system of interlinked signalling feedback loops that controls key aspects of limb bud initiation, progression and termination. ArticleCASPubMed 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. Development124, 2235–2244 (1997). ArticleCASPubMed Google Scholar
Sun, X., Mariani, F. V. & Martin, G. R. Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature418, 501–508 (2002). ArticleCASPubMed Google Scholar
Dudley, A. T., Ros, M. A. & Tabin, C. J. A re-examination of proximodistal patterning during vertebrate limb development. Nature418, 539–544 (2002). ArticleCASPubMed Google Scholar
Mercader, N. et al. Opposing RA and FGF signals control proximodistal vertebrate limb development through regulation of Meis genes. Development127, 3961–3970 (2000). ArticleCASPubMed Google Scholar
Capdevila, J., Tsukui, T., Rodriquez Esteban, C., Zappavigna, V. & Izpisúa Belmonte, J. C. Control of vertebrate limb outgrowth by the proximal factor Meis2 and distal antagonism of BMPs by Gremlin. Mol. Cell4, 839–849 (1999). ArticleCASPubMed Google Scholar
Niederreither, K., Vermot, J., Schuhbaur, B., Chambon, P. & Dolle, P. Embryonic retinoic acid synthesis is required for forelimb growth and anteroposterior patterning in the mouse. Development129, 3563–3574 (2002). ArticleCASPubMed Google Scholar
Yashiro, K. et al. Regulation of retinoic acid distribution is required for proximodistal patterning and outgrowth of the developing mouse limb. Dev. Cell6, 411–422 (2004). ArticleCASPubMed Google Scholar
Galloway, J. L., Delgado, I., Ros, M. A. & Tabin, C. J. A reevaluation of X-irradiation-induced phocomelia and proximodistal limb patterning. Nature460, 400–404 (2009). This study used molecular analysis in combination with lineage tracing to show the effects of X-ray irradiation on chicken limb buds. The resulting phenotypes had been previously interpreted in favour of the progress-zone model; this paper showed that they are not patterning defects but instead reflect the time-dependent loss of specified skeletal progenitors. This might also be true for other presumed patterning defects. ArticleCASPubMedPubMed Central Google Scholar
Zhao, X. et al. Retinoic acid promotes limb induction through effects on body axis extension but is unnecessary for limb patterning. Curr. Biol.19, 1050–1057 (2009). ArticleCASPubMedPubMed Central Google Scholar
Tabin, C. & Wolpert, L. Rethinking the proximodistal axis of the vertebrate limb in the molecular era. Genes Dev.21, 1433–1442 (2007). ArticleCASPubMed Google Scholar
ten Berge, D., Brugmann, S. A., Helms, J. A. & Nusse, R. Wnt and FGF signals interact to coordinate growth with cell fate specification during limb development. Development135, 3247–3257 (2008). An analysis of the role of e-WNT signalling in mouse limb buds and in cultured limb bud cells that shows that the interplay of FGFs and WNTs controls the proliferative expansion of the multipotent mesenchymal progenitors by maintaining them in an undifferentiated state. Cells that are no longer exposed to either of these signals will differentiate into chondrocytes, whereas continued exposure to WNTs but not FGFs diverts them to soft-tissue lineages. ArticleCASPubMed Google Scholar
Hill, T. P., Spater, D., Taketo, M. M., Birchmeier, W. & Hartmann, C. Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev. Cell8, 727–738 (2005). ArticleCASPubMed Google Scholar
Tickle, C. The number of polarizing region cells required to specifiy additional digits in the developing chick wing. Nature289, 295–298 (1981). ArticleCASPubMed Google Scholar
Wolpert, L. Positional information and the spatial pattern of cellular differentiation. J. Theor. Biol.25, 1–47 (1969). ArticleCASPubMed Google Scholar
Riddle, R. D., Johnson, R. L., Laufer, E. & Tabin, C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell75, 1401–1416 (1993). ArticleCASPubMed Google Scholar
Chiang, C. et al. Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function. Dev. Biol.236, 421–435 (2001). ArticleCASPubMed Google Scholar
Kraus, P., Fraidenraich, D. & Loomis, C. A. Some distal limb structures develop in mice lacking Sonic hedgehog signaling. Mech. Dev.100, 45–58 (2001). ArticleCASPubMed Google Scholar
Koshiba-Takeuchi, K. et al. Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart. Nature Genet.38, 175–183 (2006). ArticleCASPubMed Google Scholar
Montavon, T., Le Garrec, J. F., Kerszberg, M. & Duboule, D. Modeling Hox gene regulation in digits: reverse collinearity and the molecular origin of thumbness. Genes Dev.22, 346–359 (2008). ArticleCASPubMedPubMed Central Google Scholar
Tarchini, B., Duboule, D. & Kmita, M. Regulatory constraints in the evolution of the tetrapod limb anterior–posterior polarity. Nature443, 985–988 (2006). ArticleCASPubMed 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. Development133, 2263–2273 (2006). ArticleCASPubMed Google Scholar
te Welscher, P., Fernandez-Teran, M., Ros, M. A. & Zeller, R. Mutual genetic antagonism involving GLI3 and dHAND prepatterns the vertebrate limb bud mesenchyme prior to SHH signaling. Genes Dev.16, 421–426 (2002). ArticleCASPubMedPubMed Central Google Scholar
Rallis, C., Del Buono, J. & Logan, M. P. Tbx3 can alter limb position along the rostrocaudal axis of the developing embryo. Development132, 1961–1970 (2005). ArticleCASPubMed Google Scholar
Yang, Y. et al. Relationship between dose, distance and time in _Sonic Hedgehog_-mediated regulation of anteroposterior polarity in the chick limb. Development124, 4393–4404 (1997). ArticleCASPubMed Google Scholar
Wang, B., Fallon, J. F. & Beachy, P. A. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell100, 423–434 (2000). ArticleCASPubMed Google Scholar
Hui, C. & Joyner, A. A mouse model of Greig cephalo-polysyndactyly syndrome: the extra-toesJ mutation contains an intragenic deletion of the Gli3 gene. Nature Genet.3, 241–246 (1993). ArticleCASPubMed Google Scholar
Schimmang, T., Lemaistre, M., Vortkamp, A. & Rüther, U. Expression of the zinc finger gene Gli3 is affected in the morphogenetic mouse mutant extra-toes (Xt). Development116, 799–804 (1992). ArticleCASPubMed Google Scholar
Litingtung, Y., Dahn, R. D., Li, Y., Fallon, J. F. & Chiang, C. Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature418, 979–983 (2002). ArticleCASPubMed Google Scholar
te Welscher, P. et al. Progression of vertebrate limb development through SHH-mediated counteraction of GLI3. Science298, 827–830 (2002). ArticleCASPubMed Google Scholar
Li, Y., Zhang, H., Litingtung, Y. & Chiang, C. Cholesterol modification restricts the spread of Shh gradient in the limb bud. Proc. Natl Acad. Sci. USA103, 6548–6553 (2006). ArticleCASPubMedPubMed Central Google Scholar
Ahn, S. & Joyner, A. L. Dynamic changes in the response of cells to positive hedgehog signaling during mouse limb patterning. Cell118, 505–516 (2004). ArticleCASPubMed Google Scholar
Harfe, B. D. et al. Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell118, 517–528 (2004). Using recombinase-mediated cell lineage marking in mouse limb buds, this study established that descendants ofShh-expressing cells give rise to the two posterior-most digits and contribute to digit 3. It reveals that only specification of digit 2 depends on paracrine SHH signalling. In summary, AP identities are specified by a combination of temporally (posterior) and spatially graded (anterior) SHH signalling. ArticleCASPubMed Google Scholar
Scherz, P. J., McGlinn, E., Nissim, S. & Tabin, C. J. Extended exposure to Sonic hedgehog is required for patterning the posterior digits of the vertebrate limb. Dev. Biol.308, 343–354 (2007). ArticleCASPubMedPubMed Central Google Scholar
Towers, M., Mahood, R., Yin, Y. & Tickle, C. Integration of growth and specification in chick wing digit-patterning. Nature452, 882–886 (2008). The application of specific inhibitors of either SHH signal transduction or proliferation to chicken limb buds indicated that SHH controls both the specification and proliferation of digit progenitors. These dual functions of the SHH morphogen can be temporally uncoupled, which is discussed in this paper in relation to congenital malformations and limb evolution. ArticleCASPubMed Google Scholar
Zhu, J. et al. Uncoupling Sonic hedgehog control of pattern and expansion of the developing limb bud. Dev. Cell14, 624–632 (2008). In this study, conditional inactivation ofShhat specific time points during limb organogenesis provided evidence that SHH functions early and transiently in the specification of digit identities. Specification is followed by SHH-dependent proliferative expansion. ArticleCASPubMedPubMed Central Google Scholar
Martin, P. Tissue patterning in the developing mouse limb. Int. J. Dev. Biol.34, 323–336 (1990). CASPubMed Google Scholar
Towers, M. & Tickle, C. Growing models of vertebrate limb development. Development136, 179–190 (2009). ArticleCASPubMed Google Scholar
Laufer, E., Nelson, C. E., Johnson, R. L., Morgan, B. A. & Tabin, C. Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud. Cell79, 993–1003 (1994). ArticleCASPubMed Google Scholar
Niswander, L., Jeffrey, S., Martin, G. R. & Tickle, C. A positive feedback loop coordinates growth and patterning in the vertebrate limb. Nature371, 609–612 (1994). ArticleCASPubMed Google Scholar
Michos, O. et al. _Gremlin_-mediated BMP antagonism induces the epithelial–mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis. Development131, 3401–3410 (2004). ArticleCASPubMed Google Scholar
Zuniga, A., Haramis, A. P., McMahon, A. P. & Zeller, R. Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds. Nature401, 598–602 (1999). ArticleCASPubMed Google Scholar
Nissim, S., Hasso, S. M., Fallon, J. F. & Tabin, C. J. Regulation of Gremlin expression in the posterior limb bud. Dev. Biol.299, 12–21 (2006). ArticleCASPubMed Google Scholar
Scherz, P. J., Harfe, B. D., McMahon, A. P. & Tabin, C. J. The limb bud Shh–Fgf feedback loop is terminated by expansion of former ZPA cells. Science305, 396–399 (2004). ArticleCASPubMed Google Scholar
Verheyden, J. M. & Sun, X. An Fgf/Gremlin inhibitory feedback loop triggers termination of limb bud outgrowth. Nature454, 638–641 (2008). This paper identified the FGF inhibitory loop in mouse limb buds that induces the shutdown ofGrem1expression and of the SHH–GREM1–FGF e–m feedback loop, which controls correct temporal self-termination of chicken and mouse limb bud outgrowth. ArticleCASPubMedPubMed Central Google Scholar
Zuniga, A. & Zeller, R. Gli3 (Xt) and formin (ld) participate in the positioning of the polarising region and control of posterior limb-bud identity. Development126, 13–21 (1999). ArticleCASPubMed Google Scholar
Tickle, C. & Munsterberg, A. Vertebrate limb development — the early stages in chick and mouse. Curr. Opin. Genet. Dev.11, 476–481 (2001). ArticleCASPubMed Google Scholar
Zeller, R. & Duboule, D. Dorso-ventral limb polarity and origin of the ridge: on the fringe of independence? Bioessays19, 541–546 (1997). ArticleCASPubMed Google Scholar
Arques, C. G., Doohan, R., Sharpe, J. & Torres, M. Cell tracing reveals a dorsoventral lineage restriction plane in the mouse limb bud mesenchyme. Development134, 3713–3722 (2007). ArticleCASPubMed Google Scholar
Vargesson, N., Clarke, J. D. W., Vincent, K., Coles, C. & Wolpert, L. Cell fate in the chick limb bud and relationship to gene expression. Development124, 1909–1918 (1997). ArticleCASPubMed Google Scholar
Selever, J., Liu, W., Lu, M. F., Behringer, R. R. & Martin, J. F. Bmp4 in limb bud mesoderm regulates digit pattern by controlling AER development. Dev. Biol.276, 268–279 (2004). ArticleCASPubMed Google Scholar
Drossopoulou, G. et al. A model for anteroposterior patterning of the vertebrate limb based on sequential long- and short-range Shh signalling and Bmp signalling. Development127, 1337–1348 (2000). ArticleCASPubMed Google Scholar
Dahn, R. D. & Fallon, J. F. Interdigital regulation of digit identity and homeotic transformation by modulated BMP signaling. Science289, 438–441 (2000). ArticleCASPubMed Google Scholar
Suzuki, T., Hasso, S. M. & Fallon, J. F. Unique SMAD1/5/8 activity at the phalanx-forming region determines digit identity. Proc. Natl Acad. Sci. USA105, 4185–4190 (2008). An analysis of chicken leg buds at an advanced developmental stage that indicated that the PFRs located at the distal tip of each of the four digits are characterized by a unique signature of phospho-SMAD activities. Changes in phospho-SMAD activities correlated with altered digit identities. ArticleCASPubMedPubMed Central Google Scholar
Sanz-Ezquerro, J. J. & Tickle, C. Fgf signaling controls the number of phalanges and tip formation in developing digits. Curr. Biol.13, 1830–1836 (2003). ArticleCASPubMed Google Scholar
Kawakami, Y. et al. Sall genes regulate region-specific morphogenesis in the mouse limb by modulating Hox activities. Development136, 585–594 (2009). ArticleCASPubMedPubMed Central Google Scholar
Macias, D. et al. Role of BMP-2 and OP-1 (BMP-7) in programmed cell death and skeletogenesis during chick limb development. Development124, 1109–1117 (1997). ArticleCASPubMed Google Scholar
Bandyopadhyay, A. et al. Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet.2, e216 (2006). ArticlePubMedPubMed CentralCAS Google Scholar
Hockman, D. et al. A second wave of Sonic hedgehog expression during the development of the bat limb. Proc. Natl Acad. Sci. USA105, 16982–16987 (2008). ArticleCASPubMedPubMed Central 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). ArticlePubMed Google Scholar
Alberch, P. & Gale, E. A. Size dependence during the development of the amphibian foot. Colchicine-induced digital loss and reduction. J. Embryol. Exp. Morphol.76, 177–197 (1983). CASPubMed Google Scholar
Sakamoto, K. et al. Heterochronic shift in _Hox_-mediated activation of Sonic hedgehog leads to morphological changes during fin development. PLoS ONE4, e5121 (2009). ArticlePubMedPubMed CentralCAS Google Scholar
Sagai, T. et al. Phylogenetic conservation of a limb-specific, _cis_-acting regulator of Sonic hedgehog (Shh). Mamm. Genome15, 23–34 (2004). ArticleCASPubMed Google Scholar
Cohn, M. J. & Tickle, C. Developmental basis of limblessness and axial patterning in snakes. Nature399, 474–479 (1999). ArticleCASPubMed Google Scholar
Boot, M. J. et al. In vitro whole-organ imaging: 4D quantification of growing mouse limb buds. Nature Methods5, 609–612 (2008). ArticleCASPubMed 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). This study is a first important step towards identifying the range of genes for which expression is controlled by SHH signalling during mouse limb bud development. Using an epitope-tagged GLI3R transgene, targetcis-regulatory region genes and associated candidate genes were identified by combining chromatin immunoprecipitation with transcriptional profiling. ArticleCASPubMedPubMed Central Google Scholar
Tzchori, I. et al. LIM homeobox transcription factors integrate signaling events that control three-dimensional limb patterning and growth. Development136, 1375–1385 (2009). ArticleCASPubMedPubMed Central Google Scholar
Mao, J., McGlinn, E., Huang, P., Tabin, C. J. & McMahon, A. P. Fgf-dependent Etv4/5 activity is required for posterior restriction of Sonic hedgehog and promoting outgrowth of the vertebrate limb. Dev. Cell16, 600–606 (2009). ArticleCASPubMedPubMed Central Google Scholar
Zhang, Z., Verheyden, J. M., Hassell, J. A. & Sun, X. FGF-regulated Etv genes are essential for repressing Shh expression in mouse limb buds. Dev. Cell16, 607–613 (2009). ArticleCASPubMedPubMed Central Google Scholar
Barna, M. & Niswander, L. Visualization of cartilage formation: insight into cellular properties of skeletal progenitors and chondrodysplasia syndromes. Dev. Cell12, 931–941 (2007). ArticleCASPubMed Google Scholar
De Robertis, E. M. Spemann's organizer and self-regulation in amphibian embryos. Nature Rev. Mol. Cell Biol.7, 296–302 (2006). ArticleCAS Google Scholar
Dessaud, E., McMahon, A. P. & Briscoe, J. Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network. Development135, 2489–2503 (2008). ArticleCASPubMed Google Scholar
Dessaud, E. et al. Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism. Nature450, 717–720 (2007). ArticleCASPubMed Google Scholar
Eaton, S. Release and trafficking of lipid-linked morphogens. Curr. Opin. Genet. Dev.16, 17–22 (2006). ArticleCASPubMed Google Scholar
Piddini, E. & Vincent, J. P. Interpretation of the wingless gradient requires signaling-induced self-inhibition. Cell136, 296–307 (2009). ArticleCASPubMed Google Scholar
Affolter, M. & Basler, K. The Decapentaplegic morphogen gradient: from pattern formation to growth regulation. Nature Rev. Genet.8, 663–674 (2007). ArticleCASPubMed Google Scholar
Callejo, A., Torroja, C., Quijada, L. & Guerrero, I. Hedgehog lipid modifications are required for Hedgehog stabilization in the extracellular matrix. Development133, 471–483 (2006). ArticleCASPubMed Google Scholar
Grandel, H. & Schulte-Merker, S. The development of the paired fins in the zebrafish (Danio rerio). Mech. Dev.79, 99–120 (1998). ArticleCASPubMed Google Scholar
Gibert, Y., Gajewski, A., Meyer, A. & Begemann, G. Induction and prepatterning of the zebrafish pectoral fin bud requires axial retinoic acid signaling. Development133, 2649–2659 (2006). ArticleCASPubMed Google Scholar
Norton, W. H., Ledin, J., Grandel, H. & Neumann, C. J. HSPG synthesis by zebrafish Ext2 and Extl3 is required for Fgf10 signalling during limb development. Development132, 4963–4973 (2005). ArticleCASPubMed Google Scholar
Neumann, C. J., Grandel, H., Gaffield, W., Schulte-Merker, S. & Nusslein-Volhard, C. Transient establishment of anteroposterior polarity in the zebrafish pectoral fin bud in the absence of sonic hedgehog activity. Development126, 4817–4826 (1999). ArticleCASPubMed Google Scholar
Prykhozhij, S. V. & Neumann, C. J. Distinct roles of Shh and Fgf signaling in regulating cell proliferation during zebrafish pectoral fin development. BMC Dev. Biol.8, 91 (2008). ArticlePubMedPubMed CentralCAS 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. Nature447, 473–476 (2007). ArticleCASPubMed 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 ONE2, e754 (2007). ArticlePubMedPubMed CentralCAS Google Scholar
Case, D. T., Hill, R. J., Merbs, C. F. & Fong, M. Polydactyly in the prehistoric American Southwest. Int. J. Osteoarcheol.16, 221–235 (2006). Article Google Scholar
Heus, H. C. et al. A physical and transcriptional map of the preaxial polydactyly locus on chromosome 7q36. Genomics57, 342–351 (1999). ArticleCASPubMed Google Scholar
Lettice, L. A. et al. Disruption of a long-range _cis_-acting regulator for Shh causes preaxial polydactyly. Proc. Natl Acad. Sci. USA99, 7548–7553 (2002). ArticleCASPubMedPubMed Central Google Scholar
Lettice, L. A. et al. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum. Mol. Genet.12, 1725–1735 (2003). ArticleCASPubMed 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). ArticleCASPubMed Google Scholar
Park, K., Kang, J., Subedi, K. P., Ha, J.-H. & Park, C. Canine polydactyl mutations with heterogeneous origin in the conserved intronic sequence of Lmbr1 gene. Genetics179, 2163–2172 (2008). ArticleCASPubMedPubMed Central 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. Development132, 797–803 (2005). ArticleCASPubMed Google Scholar
Lettice, L. A. & Hill, R. E. Preaxial polydactyly: a model for defective long-range regulation in congenital abnormalities. Curr. Opin. Genet. Dev.15, 294–300 (2005). ArticleCASPubMed Google Scholar
Amano, T. et al. Chromosomal dynamics at the Shh locus: limb bud-specific differential regulation of competence and active transcription. Dev. Cell16, 47–57 (2009). ArticleCASPubMed Google Scholar