Gene Symbol: Hoxd12
Description: homeobox D12
Alias: Hox-4.7, Hox-5.6, homeobox protein Hox-D12, homeo box D12, homeobox protein Hox-4.7, homeobox protein Hox-5.6
Species: mouse
Products:     Hoxd12

Top Publications

  1. Dolle P, Izpisua Belmonte J, Falkenstein H, Renucci A, Duboule D. Coordinate expression of the murine Hox-5 complex homoeobox-containing genes during limb pattern formation. Nature. 1989;342:767-72 pubmed
  2. Spitz F, Gonzalez F, Duboule D. A global control region defines a chromosomal regulatory landscape containing the HoxD cluster. Cell. 2003;113:405-17 pubmed
    ..These domains were interrupted in the Ulnaless mutation, a balanced inversion that modified the topography of the locus. We discuss the heuristic value of these results in term of locus specific versus gene-specific regulation. ..
  3. Zakany J, Duboule D. Synpolydactyly in mice with a targeted deficiency in the HoxD complex. Nature. 1996;384:69-71 pubmed
    ..8), may involve the loss of function of several Hoxd genes. These results indicate the existence of a functional hierarchy among these genes and provide us with an animal model to study human digit malformations. ..
  4. Knezevic V, De Santo R, Schughart K, Huffstadt U, Chiang C, Mahon K, et al. Hoxd-12 differentially affects preaxial and postaxial chondrogenic branches in the limb and regulates Sonic hedgehog in a positive feedback loop. Development. 1997;124:4523-36 pubmed
    ..Together these results suggest that certain 5' Hoxd genes directly amplify the posterior Shh polarizing signal in a reinforcing positive feedback loop during limb bud outgrowth...
  5. Chiang C, Litingtung Y, Harris M, Simandl B, Li Y, Beachy P, et al. Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function. Dev Biol. 2001;236:421-35 pubmed
    ..According to this model, the limb bud signaling centers, including the zone of polarizing activity (ZPA) acting through Shh, are required to elaborate upon the axial information provided by the native limb field prepattern. ..
  6. Herault Y, Beckers J, Gerard M, Duboule D. Hox gene expression in limbs: colinearity by opposite regulatory controls. Dev Biol. 1999;208:157-65 pubmed
    ..their functional domains are colinear with their genomic positions within the HoxD cluster such that Hoxd13 and Hoxd12 are necessary for digit development, whereas Hoxd11 and Hoxd10 are involved in making forearms...
  7. Spitz F, Gonzalez F, Peichel C, Vogt T, Duboule D, Zakany J. Large scale transgenic and cluster deletion analysis of the HoxD complex separate an ancestral regulatory module from evolutionary innovations. Genes Dev. 2001;15:2209-14 pubmed
    ..Accordingly, deletion of the entire cluster abolished axial expression, whereas recently acquired regulatory controls were preserved. ..
  8. Hill P, Götz K, Ruther U. A SHH-independent regulation of Gli3 is a significant determinant of anteroposterior patterning of the limb bud. Dev Biol. 2009;328:506-16 pubmed publisher
    ..Furthermore, we present evidence that the anteroposterior grading of GLI3 activity by the action of SHH is supported by a prototype patterning, which regulates Gli3 independently from SHH. ..
  9. Chen Y, Knezevic V, Ervin V, Hutson R, Ward Y, Mackem S. Direct interaction with Hoxd proteins reverses Gli3-repressor function to promote digit formation downstream of Shh. Development. 2004;131:2339-47 pubmed
    ..We show that Hoxd12 interacts genetically and physically with Gli3, and can convert the Gli3 repressor into an activator of Shh target ..

More Information


  1. Davis A, Capecchi M. A mutational analysis of the 5' HoxD genes: dissection of genetic interactions during limb development in the mouse. Development. 1996;122:1175-85 pubmed
    ..The 5' Hox genes could therefore act as a major permissive genetic milieu that has been exploited by evolutionary adaptation to form the tetrapod limbs. ..
  2. Tarchini B, Duboule D. Control of Hoxd genes' collinearity during early limb development. Dev Cell. 2006;10:93-103 pubmed
  3. Zakany J, Kmita M, Duboule D. A dual role for Hox genes in limb anterior-posterior asymmetry. Science. 2004;304:1669-72 pubmed
    ..deficiency in the mouse HoxD cluster, we found that a perturbation in the early collinear expression of Hoxd11, Hoxd12, and Hoxd13 in limb buds led to a loss of asymmetry...
  4. Buscher D, Bosse B, Heymer J, Ruther U. Evidence for genetic control of Sonic hedgehog by Gli3 in mouse limb development. Mech Dev. 1997;62:175-82 pubmed
    ..This data suggest that Gli3 is a regulator of Shh expression in mouse limb development. ..
  5. Herault Y, Beckers J, Kondo T, Fraudeau N, Duboule D. Genetic analysis of a Hoxd-12 regulatory element reveals global versus local modes of controls in the HoxD complex. Development. 1998;125:1669-77 pubmed
    ..These results support a model whereby global as well as local regulatory influences are necessary to build up the complex expression patterns of Hoxd genes during limb development. ..
  6. Izpisua Belmonte J, Falkenstein H, Dolle P, Renucci A, Duboule D. Murine genes related to the Drosophila AbdB homeotic genes are sequentially expressed during development of the posterior part of the body. EMBO J. 1991;10:2279-89 pubmed
    ..Furthermore, the possible role of 'temporal colinearity' in the ontogeny of all coelomic (metamerized) metazoans showing a temporal anteroposterior morphogenetic progression is addressed. ..
  7. Gerard M, Chen J, Gronemeyer H, Chambon P, Duboule D, Zakany J. In vivo targeted mutagenesis of a regulatory element required for positioning the Hoxd-11 and Hoxd-10 expression boundaries. Genes Dev. 1996;10:2326-34 pubmed
    ..These results illustrate the sharing, in cis, of a single regulatory element in order to establish the expression boundaries of two neighboring Hoxd genes. ..
  8. Kmita M, Fraudeau N, Herault Y, Duboule D. Serial deletions and duplications suggest a mechanism for the collinearity of Hoxd genes in limbs. Nature. 2002;420:145-50 pubmed
  9. Herault Y, Rassoulzadegan M, Cuzin F, Duboule D. Engineering chromosomes in mice through targeted meiotic recombination (TAMERE). Nat Genet. 1998;20:381-4 pubmed
    ..The high frequency of such targeted exchanges in vivo makes TAMERE a powerful genetic tool applicable to research areas in which complex genomic modifications are required. ..
  10. Delpretti S, Zakany J, Duboule D. A function for all posterior Hoxd genes during digit development?. Dev Dyn. 2012;241:792-802 pubmed publisher
    ..We also show that Hoxd10, Hoxd11, and Hoxd12 all seem to play a genuine role in digit development, though less compelling than that of Hoxd13...
  11. Kondo T, Duboule D. Breaking colinearity in the mouse HoxD complex. Cell. 1999;97:407-17 pubmed
    ..These data suggest that a regulatory element located upstream of the complex is necessary for setting up the early pattern of Hox gene colinear activation. ..
  12. Yashiro K, Zhao X, Uehara M, Yamashita K, Nishijima M, Nishino J, et al. Regulation of retinoic acid distribution is required for proximodistal patterning and outgrowth of the developing mouse limb. Dev Cell. 2004;6:411-22 pubmed
    ..These observations suggest that RA acts as a morphogen to determine proximodistal identity, and that CYP26B1 prevents apoptosis and promotes chondrocyte maturation, in the developing limb. ..
  13. Raz R, Stricker S, Gazzerro E, Clor J, Witte F, Nistala H, et al. The mutation ROR2W749X, linked to human BDB, is a recessive mutation in the mouse, causing brachydactyly, mediating patterning of joints and modeling recessive Robinow syndrome. Development. 2008;135:1713-23 pubmed publisher
    ..Therefore, Ror2(W749FLAG/W749FLAG) mice represent a postnatal model for RRS, provide insight into the mechanism of joint specification, and uncover novel roles of Ror2 in the mouse...
  14. Montavon T, Soshnikova N, Mascrez B, Joye E, Thevenet L, Splinter E, et al. A regulatory archipelago controls Hox genes transcription in digits. Cell. 2011;147:1132-45 pubmed publisher
  15. Patterson L, Pembaur M, Potter S. Hoxa11 and Hoxd11 regulate branching morphogenesis of the ureteric bud in the developing kidney. Development. 2001;128:2153-61 pubmed
  16. Maatouk D, Choi K, Bouldin C, Harfe B. In the limb AER Bmp2 and Bmp4 are required for dorsal-ventral patterning and interdigital cell death but not limb outgrowth. Dev Biol. 2009;327:516-23 pubmed publisher
    ..Our data suggests that AER expression of Bmp2 and Bmp4 is required for digit and dorsal-ventral patterning but surprisingly not for limb outgrowth...
  17. Burke A, Nelson C, Morgan B, Tabin C. Hox genes and the evolution of vertebrate axial morphology. Development. 1995;121:333-46 pubmed
    ..The recognition of mechanistic homology supports the historical homology of basic patterning mechanisms between all organisms that share these genes. ..
  18. Crackower M, Motoyama J, Tsui L. Defect in the maintenance of the apical ectodermal ridge in the Dactylaplasia mouse. Dev Biol. 1998;201:78-89 pubmed
    ..Moreover, the data suggest that the role of the AER maintenance factor is to promote cell proliferation in the ridge. Based on our findings, we propose a model for AER maintenance in the vertebrate limb. ..
  19. Hill P, Wang B, Ruther U. The molecular basis of Pallister Hall associated polydactyly. Hum Mol Genet. 2007;16:2089-96 pubmed
    ..The presented findings help to understand the previously enigmatic emergence of Pallister-Hall associated polydactyly and thus add to the understanding of the pathogenic mode of the action of GLI3(PHS). ..
  20. Verheyden J, Lewandoski M, Deng C, Harfe B, Sun X. Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning. Development. 2005;132:4235-45 pubmed
    ..Our study of these two Fgfr1 conditional mutants has elucidated the multiple roles of FGFR1 in limb bud establishment, growth and patterning. ..
  21. Shen W, Montgomery J, Rozenfeld S, Moskow J, Lawrence H, Buchberg A, et al. AbdB-like Hox proteins stabilize DNA binding by the Meis1 homeodomain proteins. Mol Cell Biol. 1997;17:6448-58 pubmed
    ..DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. ..
  22. Makino S, Zhulyn O, Mo R, Puviindran V, Zhang X, Murata T, et al. T396I mutation of mouse Sufu reduces the stability and activity of Gli3 repressor. PLoS ONE. 2015;10:e0119455 pubmed publisher
    ..This implies a novel Sufu-mediated mechanism in which Gli2 activator and Gli3 repressor are differentially regulated. ..
  23. Schorderet P, Duboule D. Structural and functional differences in the long non-coding RNA hotair in mouse and human. PLoS Genet. 2011;7:e1002071 pubmed publisher
    ..Alternatively, redundant or compensatory mechanisms may mask its function when studied under physiological conditions. ..
  24. Boulet A, Capecchi M. Duplication of the Hoxd11 gene causes alterations in the axial and appendicular skeleton of the mouse. Dev Biol. 2002;249:96-107 pubmed
    ..Interestingly, the insertion of an additional Hoxd11 locus into the HoxD complex does not appear to affect the expression patterns of the neighboring Hoxd10, -d12, or -d13 genes. ..
  25. Guha U, Gomes W, Kobayashi T, Pestell R, Kessler J. In vivo evidence that BMP signaling is necessary for apoptosis in the mouse limb. Dev Biol. 2002;249:108-20 pubmed
    ..These abnormalities were rescued by coexpressing BMP4 under the same promoter in double transgenic mice, suggesting that the limb abnormalities are a direct effect of inhibiting BMP signaling. ..
  26. Hecksher Sørensen J, Hill R, Lettice L. Double labeling for whole-mount in situ hybridization in mouse. Biotechniques. 1998;24:914-6, 918 pubmed
  27. Kamiyama N, Seki R, Yokoyama H, Tamura K. Heterochronically early decline of Hox expression prior to cartilage formation in the avian hindlimb zeugopod. Dev Growth Differ. 2012;54:619-32 pubmed publisher
    ..produced from a region that is defined as the fixed Hox code, we examined spatial and temporal patterns of Hoxd11/Hoxd12 expression in the developing limb bud, which defines the region from which the fibula emerges, in comparison with ..
  28. Chan D, Laufer E, Tabin C, Leder P. Polydactylous limbs in Strong's Luxoid mice result from ectopic polarizing activity. Development. 1995;121:1971-8 pubmed
    ..We suggest that the 1st gene product is involved in anteroposterior axis formation during normal limb development. ..
  29. Kondo T, Zakany J, Duboule D. Control of colinearity in AbdB genes of the mouse HoxD complex. Mol Cell. 1998;1:289-300 pubmed
  30. Zuniga A, Zeller R. Gli3 (Xt) and formin (ld) participate in the positioning of the polarising region and control of posterior limb-bud identity. Development. 1999;126:13-21 pubmed
    ..Concurrently, Gli3 functions independently of formin during initial posterior nesting of 5'HoxD domains, whereas their subsequent distal restriction and anterior expansion depends on genetic interaction of Gli3 and formin. ..
  31. Sheth R, Marcon L, Bastida M, Junco M, Quintana L, DAHN R, et al. Hox genes regulate digit patterning by controlling the wavelength of a Turing-type mechanism. Science. 2012;338:1476-80 pubmed publisher
    ..The phenotypic similarity with fish-fin endoskeleton patterns suggests that the pentadactyl state has been achieved through modification of an ancestral Turing-type mechanism. ..
  32. Dupé V, Ghyselinck N, Thomazy V, Nagy L, Davies P, Chambon P, et al. Essential roles of retinoic acid signaling in interdigital apoptosis and control of BMP-7 expression in mouse autopods. Dev Biol. 1999;208:30-43 pubmed
    ..Therefore, RA may exert some of its effects on anteroposterior autopod patterning through controlling BMP-7 expression. ..
  33. Kmita M, Kondo T, Duboule D. Targeted inversion of a polar silencer within the HoxD complex re-allocates domains of enhancer sharing. Nat Genet. 2000;26:451-4 pubmed
    ..This polar silencer appears to limit the number of genes that respond to one type of regulation and thus indicates how separate regulatory domains may be implemented within intricate gene clusters. ..
  34. Akiyama R, Kawakami H, Taketo M, Evans S, Wada N, Petryk A, et al. Distinct populations within Isl1 lineages contribute to appendicular and facial skeletogenesis through the ?-catenin pathway. Dev Biol. 2014;387:37-48 pubmed publisher
  35. Raines A, Magella B, Adam M, Potter S. Key pathways regulated by HoxA9,10,11/HoxD9,10,11 during limb development. BMC Dev Biol. 2015;15:28 pubmed publisher
    ..The RNA-Seq analysis of specific compartments of the normal and mutant limbs defines the multiple key perturbed pathways downstream of these Hox genes. ..
  36. Bowers M, Eng L, Lao Z, Turnbull R, Bao X, Riedel E, et al. Limb anterior-posterior polarity integrates activator and repressor functions of GLI2 as well as GLI3. Dev Biol. 2012;370:110-24 pubmed publisher
    ..Taken together, our data suggest that establishment of a complete range of AP positional identities in the limb requires integration of the spatial distribution, timing, and dosage of GLI2 and GLI3 activators and repressors. ..
  37. Huang B, Trofka A, Furusawa A, Norrie J, Rabinowitz A, Vokes S, et al. An interdigit signalling centre instructs coordinate phalanx-joint formation governed by 5'Hoxd-Gli3 antagonism. Nat Commun. 2016;7:12903 pubmed publisher
    ..We propose that 5'Hoxd genes and Gli3 are part of an interdigital signalling centre that sets net Bmp signalling levels from different interdigits to coordinately regulate phalanx and joint formation. ..
  38. 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. Development. 2002;129:3563-74 pubmed
    ..We suggest that RA signaling cooperates with a posteriorly restricted factor such as dHand, to generate a functional zone of polarizing activity (ZPA). ..
  39. Lewandoski M, Sun X, Martin G. Fgf8 signalling from the AER is essential for normal limb development. Nat Genet. 2000;26:460-3 pubmed
    ..Our data identify Fgf8 as the only known AER-Fgf individually necessary for normal limb development, and provide insight into the function of Fgf signalling from the AER in the normal outgrowth and patterning of the limb. ..
  40. Xu X, Weinstein M, Li C, Deng C. Fibroblast growth factor receptors (FGFRs) and their roles in limb development. Cell Tissue Res. 1999;296:33-43 pubmed
    ..In this review we discuss recent work with FGF receptors to illustrate mechanisms, through which the FGF/FGFR signals specify vertebrate limb initiation, outgrowth and patterning. ..
  41. Hulander M, Wurst W, Carlsson P, Enerback S. The winged helix transcription factor Fkh10 is required for normal development of the inner ear. Nat Genet. 1998;20:374-6 pubmed
    ..These findings implicate Fkh10 as an early regulator necessary for development of both cochlea and vestibulum and identify its human homologue FKHL10 as a previously unknown candidate deafness gene at 5q34. ..
  42. Zakany J, Fromental Ramain C, Warot X, Duboule D. Regulation of number and size of digits by posterior Hox genes: a dose-dependent mechanism with potential evolutionary implications. Proc Natl Acad Sci U S A. 1997;94:13695-700 pubmed
    ..Thus, transition through a polydactylous limb before reaching and stabilizing the pentadactyl pattern may have relied, at least in part, on asynchronous and independent changes in the regulation of HoxA and HoxD gene complexes. ..
  43. Delgado I, Dominguez Frutos E, Schimmang T, Ros M. The incomplete inactivation of Fgf8 in the limb ectoderm affects the morphogenesis of the anterior autopod through BMP-mediated cell death. Dev Dyn. 2008;237:649-58 pubmed publisher
    ..These limbs also exhibit an abnormal area of cell death at the anterior forelimb autopod, overlapping with an ectopic domain of Bmp7 expression, which can explain the abnormal morphogenesis of the anterior autopod. ..
  44. Krebs O, Schreiner C, Scott W, Bell S, Robbins D, Goetz J, et al. Replicated anterior zeugopod (raz): a polydactylous mouse mutant with lowered Shh signaling in the limb bud. Development. 2003;130:6037-47 pubmed
    ..We propose that the double anterior zeugopod and symmetrical central polydactyly are due to an increased and uniform concentration of the Gli3 repressor form because of lowered Shh signaling. ..
  45. Butterfield N, Metzis V, McGlinn E, Bruce S, Wainwright B, Wicking C. Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb. Development. 2009;136:3515-24 pubmed publisher
    ..These results establish the importance of the downstream consequences of Hh pathway repression, and identify Ptc1 as a key player in limb patterning even prior to the onset of Shh expression. ..
  46. Tschopp P, Duboule D. A regulatory 'landscape effect' over the HoxD cluster. Dev Biol. 2011;351:288-96 pubmed publisher
    ..Proximal limbs were also affected, suggesting that this 'landscape effect' is generic and impacts upon regulatory mechanisms of various qualities and evolutionary origins. ..
  47. Albrecht A, Schwabe G, Stricker S, Böddrich A, Wanker E, Mundlos S. The synpolydactyly homolog (spdh) mutation in the mouse -- a defect in patterning and growth of limb cartilage elements. Mech Dev. 2002;112:53-67 pubmed
    ..Abnormal chondrocyte differentiation and proliferation persisted after birth and correlated with the expression of the mutant Hoxd13 and other Hox-genes during late-embryonic and postnatal growth. ..
  48. Herault Y, Fraudeau N, Zakany J, Duboule D. Ulnaless (Ul), a regulatory mutation inducing both loss-of-function and gain-of-function of posterior Hoxd genes. Development. 1997;124:3493-500 pubmed
  49. Koyama E, Yamaai T, Iseki S, Ohuchi H, Nohno T, Yoshioka H, et al. Polarizing activity, Sonic hedgehog, and tooth development in embryonic and postnatal mouse. Dev Dyn. 1996;206:59-72 pubmed
    ..Given its subsequent association with differentiating ameloblasts, Shh probably participates also in cytogenetic events during odontogenesis. ..
  50. Akiyama H, Stadler H, Martin J, Ishii T, Beachy P, Nakamura T, et al. Misexpression of Sox9 in mouse limb bud mesenchyme induces polydactyly and rescues hypodactyly mice. Matrix Biol. 2007;26:224-33 pubmed
    ..These results provide evidence that Sox9 induces ectopic chondrogenesis in mesenchymal cells and strongly suggest that its expression may be regulated by Hox genes during limb bud development...
  51. Bimonte S, De Angelis A, Quagliata L, Giusti F, Tammaro R, Dallai R, et al. Ofd1 is required in limb bud patterning and endochondral bone development. Dev Biol. 2011;349:179-91 pubmed publisher
    ..Our data demonstrate that Ofd1 plays a role in regulating digit number and identity during limb and skeletal patterning increasing insight on the functional role of primary cilia during development. ..
  52. Sharpe J, Lettice L, Hecksher Sorensen J, Fox M, Hill R, Krumlauf R. Identification of sonic hedgehog as a candidate gene responsible for the polydactylous mouse mutant Sasquatch. Curr Biol. 1999;9:97-100 pubmed
    ..The Shh, Fgf4, Fgf8, Hoxd12 and Hoxd13 genes were all ectopically expressed in the anterior region of affected limb buds...
  53. Bruneau S, Johnson K, Yamamoto M, Kuroiwa A, Duboule D. The mouse Hoxd13(spdh) mutation, a polyalanine expansion similar to human type II synpolydactyly (SPD), disrupts the function but not the expression of other Hoxd genes. Dev Biol. 2001;237:345-53 pubmed
    ..Developmental studies indicate that the morphological effect is mostly due to a severe retardation in the growth and ossification of the bony elements, in agreement with a general impairment in the function of posterior Hoxd genes. ..