Genomes and Genes
Gene Symbol: Hoxd13
Description: homeobox D13
Alias: Hox-4.8, spdh, homeobox protein Hox-D13, homeo box D13, homeobox protein Hox-4.8
- Kmita M, van der Hoeven F, Zakany J, Krumlauf R, Duboule D. Mechanisms of Hox gene colinearity: transposition of the anterior Hoxb1 gene into the posterior HoxD complex. Genes Dev. 2000;14:198-211 pubmed..Furthermore, the transgene induced a transient ectopic activation of the neighboring Hoxd13 gene, without affecting other genes of the complex...
- Kmita M, Tarchini B, Duboule D, Herault Y. Evolutionary conserved sequences are required for the insulation of the vertebrate Hoxd complex in neural cells. Development. 2002;129:5521-8 pubmed..These results suggest that insulation of this important gene cluster relies, at least in part, upon a sequence-specific mechanism that displays some redundancy. ..
- 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
- 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. ..
- 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. ..
- Zhu X, Zhu H, Zhang L, Huang S, Cao J, Ma G, et al. Wls-mediated Wnts differentially regulate distal limb patterning and tissue morphogenesis. Dev Biol. 2012;365:328-38 pubmed publisher..These findings provide a comprehensive view of the role of Wnts in limb patterning and tissue morphogenesis...
- Zakany J, Duboule D. Synpolydactyly in mice with a targeted deficiency in the HoxD complex. Nature. 1996;384:69-71 pubmed..seen in a human synpolydactyly, suggesting that this syndrome, which is associated with a subtle mutation in HOXD13 (ref. 8), may involve the loss of function of several Hoxd genes...
- Sun X, Mariani F, Martin G. Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature. 2002;418:501-8 pubmed..In the complete absence of both FGF4 and FGF8 activities, limb development fails. We present a model to explain how the mutant phenotypes arise from FGF-mediated effects on limb bud size and cell survival. ..
- Wang C, Ruther U, Wang B. The Shh-independent activator function of the full-length Gli3 protein and its role in vertebrate limb digit patterning. Dev Biol. 2007;305:460-9 pubmed
- Litingtung Y, Dahn R, Li Y, Fallon J, Chiang C. Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature. 2002;418:979-83 pubmed
- Panman L, Galli A, Lagarde N, Michos O, Soete G, Zuniga A, et al. Differential regulation of gene expression in the digit forming area of the mouse limb bud by SHH and gremlin 1/FGF-mediated epithelial-mesenchymal signalling. Development. 2006;133:3419-28 pubmed..In particular, the expression of Hoxd13 depends on SHH signal transduction significantly longer than does Hoxd11 expression, revealing that the reverse co-..
- Williams T, Williams M, Heaton J, Gelehrter T, Innis J. Group 13 HOX proteins interact with the MH2 domain of R-Smads and modulate Smad transcriptional activation functions independent of HOX DNA-binding capability. Nucleic Acids Res. 2005;33:4475-84 pubmed..Among the interactors, we isolated the BMP-signaling effector Smad5, which interacted with the paralogous HOXD13 but not with HOXA11 or HOXA9, revealing unique interaction capabilities of the AbdB-like HOX proteins...
- Dolle P, Izpisua Belmonte J, Brown J, Tickle C, Duboule D. HOX-4 genes and the morphogenesis of mammalian genitalia. Genes Dev. 1991;5:1767-7 pubmed..We also show that genital tubercle mesenchyme can respecify pattern in the chicken wing bud. This finding reinforces the concept of the uniformity in the patterning mechanisms along the various axes of the body. ..
- Perriton C, Powles N, Chiang C, Maconochie M, Cohn M. Sonic hedgehog signaling from the urethral epithelium controls external genital development. Dev Biol. 2002;247:26-46 pubmed
- 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..The resulting altered balance between 'effective' Gli3 activating and repressing functions may also serve to extend the Shh activity gradient spatially or temporally...
- Podlasek C, Clemens J, Bushman W. Hoxa-13 gene mutation results in abnormal seminal vesicle and prostate development. J Urol. 1999;161:1655-61 pubmed..The similarity in expression and overlap in phenotype resulting from mutation is consistent with additive function and partial functional redundancy of Hoxa-13 and Hoxd-13 in male accessory sex organ development. ..
- 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..development, 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...
- Tarchini B, Duboule D. Control of Hoxd genes' collinearity during early limb development. Dev Cell. 2006;10:93-103 pubmed
- Hayes C, Brown J, Lyon M, Morriss Kay G. Sonic hedgehog is not required for polarising activity in the Doublefoot mutant mouse limb bud. Development. 1998;125:351-7 pubmed..of the direct Shh target genes Ptc and Gli, and induction of the downstream target genes Bmp2, Fgf4 and Hoxd13. The expression domains of all these genes extend from their normal posterior domains into the anterior part of ..
- Xu B, Wellik D. Axial Hox9 activity establishes the posterior field in the developing forelimb. Proc Natl Acad Sci U S A. 2011;108:4888-91 pubmed publisher..This Hox9 mutant phenotype is restricted to the forelimbs; mutant hindlimbs are normal, revealing fundamental differences in the patterning mechanisms governing the establishment of forelimb and hindlimb fields. ..
- Schneider I, Aneas I, Gehrke A, Dahn R, Nobrega M, Shubin N. Appendage expression driven by the Hoxd Global Control Region is an ancient gnathostome feature. Proc Natl Acad Sci U S A. 2011;108:12782-6 pubmed publisher..Our results support the notion that some of the novelties associated with tetrapod limbs arose by modification of deeply conserved cis- and trans-acting mechanisms of Hox regulation in gnathostomes. ..
- Williams T, Williams M, Innis J. Range of HOX/TALE superclass associations and protein domain requirements for HOXA13:MEIS interaction. Dev Biol. 2005;277:457-71 pubmed..We show that Hoxa13 and Hoxd13 expression does not overlap with that of Meis1-3 in the developing limb; however, coexpression occurs in the ..
- Liu A, Wang B, Niswander L. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development. 2005;132:3103-11 pubmed..In summary, our results indicate that IFT function is crucial in the control of both the positive and negative transcriptional activities of Gli proteins, and essential for Hh ligand-induced signaling cascade. ..
- Panman L, Drenth T, Tewelscher P, Zuniga A, Zeller R. Genetic interaction of Gli3 and Alx4 during limb development. Int J Dev Biol. 2005;49:443-8 pubmed..Most interestingly, the loss of the severe preaxial polydactyly characteristic of Gli3-/- limbs in double mutant embryos establishes that this type of polydactyly requires Alx4 function. ..
- Monge I, Kondo T, Duboule D. An enhancer-titration effect induces digit-specific regulatory alleles of the HoxD cluster. Dev Biol. 2003;256:212-20 pubmed..We report here that these targeted relocations behaved as hypomorphic alleles of the distantly located gene Hoxd13 and showed that posterior Hoxd genes located in cis with the integration site were down-regulated...
- van der Hoeven F, Zakany J, Duboule D. Gene transpositions in the HoxD complex reveal a hierarchy of regulatory controls. Cell. 1996;85:1025-35 pubmed..These results suggest that high order regulation controls the activation of Hox genes and highlight three important constraints responsible for the conservation of Hox gene clustering. ..
- 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. ..
- 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. ..
- Haraguchi R, Suzuki K, Murakami R, Sakai M, Kamikawa M, Kengaku M, et al. Molecular analysis of external genitalia formation: the role of fibroblast growth factor (Fgf) genes during genital tubercle formation. Development. 2000;127:2471-9 pubmed..distal urethral plate epithelium of the genital tubercle (GT) together with other markers such as the Msx1, Fgf10, Hoxd13 and Bmp4 expressed in the mesenchyme...
- Kraus P, Fraidenraich D, Loomis C. Some distal limb structures develop in mice lacking Sonic hedgehog signaling. Mech Dev. 2001;100:45-58 pubmed..The presence of distal autopod elements is consistent with weak expression of Hoxd13 in Shh(-/-) hindlimbs...
- Fromental Ramain C, Warot X, Messadecq N, LeMeur M, Dolle P, Chambon P. Hoxa-13 and Hoxd-13 play a crucial role in the patterning of the limb autopod. Development. 1996;122:2997-3011 pubmed
- 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. ..
- Williams T, Williams M, Kuick R, Misek D, McDonagh K, Hanash S, et al. Candidate downstream regulated genes of HOX group 13 transcription factors with and without monomeric DNA binding capability. Dev Biol. 2005;279:462-80 pubmed..b>HOXD13 similarly activated/repressed 6 tested candidates, demonstrating that multiple downstream genetic pathways may be ..
- Haraguchi R, Mo R, Hui C, Motoyama J, Makino S, Shiroishi T, et al. Unique functions of Sonic hedgehog signaling during external genitalia development. Development. 2001;128:4241-50 pubmed..that Shh could regulate mesenchymally expressed genes, patched 1 (Ptch1), bone morphogenetic protein 4 (Bmp4), Hoxd13 and fibroblast growth factor 10 (Fgf10), in the anlage: the genital tubercle (GT)...
- Kondo T, Zakany J, Innis J, Duboule D. Of fingers, toes and penises. Nature. 1997;390:29 pubmed
- Post L, Innis J. Altered Hox expression and increased cell death distinguish Hypodactyly from Hoxa13 null mice. Int J Dev Biol. 1999;43:287-94 pubmed..Expression of Hoxd13 was unaffected in Hoxa13-/- mice, but its domain was reduced at the anterior and posterior margins of the autopod ..
- Lin C, Yin Y, Veith G, Fisher A, Long F, Ma L. Temporal and spatial dissection of Shh signaling in genital tubercle development. Development. 2009;136:3959-67 pubmed publisher..endoderm genetically, we revealed that Shh relays its signal partly through the dUE, but regulates Hoxa13 and Hoxd13 expression independently of dUE signaling...
- Sheth R, Bastida M, Ros M. Hoxd and Gli3 interactions modulate digit number in the amniote limb. Dev Biol. 2007;310:430-41 pubmed..Our results also support the notion that an adequate balance between positive and negative effects of different Hoxd genes is required for pentadactyly. ..
- Ferrante M, Zullo A, Barra A, Bimonte S, Messaddeq N, Studer M, et al. Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification. Nat Genet. 2006;38:112-7 pubmed
- Capellini T, Di Giacomo G, Salsi V, Brendolan A, Ferretti E, Srivastava 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. 2006;133:2263-73 pubmed
- Villavicencio Lorini P, Kuss P, Friedrich J, Haupt J, Farooq M, Turkmen S, et al. Homeobox genes d11-d13 and a13 control mouse autopod cortical bone and joint formation. J Clin Invest. 2010;120:1994-2004 pubmed publisher..the hands and feet) using the mouse mutant synpolydactyly homolog (spdh), which encodes a polyalanine expansion in Hoxd13. We found that no cortical bone was formed in the autopod in spdh/spdh mice; instead, these bones underwent ..
- Bénazet J, Bischofberger M, Tiecke E, Gonçalves A, Martin J, Zuniga A, et al. A self-regulatory system of interlinked signaling feedback loops controls mouse limb patterning. Science. 2009;323:1050-3 pubmed publisher..This self-regulatory signaling network results in robust regulation of distal limb development that is able to compensate for variations by interconnectivity among the three signaling pathways. ..
- Montavon T, Le Garrec J, Kerszberg M, Duboule D. Modeling Hox gene regulation in digits: reverse collinearity and the molecular origin of thumbness. Genes Dev. 2008;22:346-59 pubmed publisher..We also show that the same model applies to the collinear regulation of Hox genes during the emergence of external genitalia, though with some differences likely illustrating the distinct functionalities of these structures in adults. ..
- Zakany J, Zacchetti G, Duboule D. Interactions between HOXD and Gli3 genes control the limb apical ectodermal ridge via Fgf10. Dev Biol. 2007;306:883-93 pubmed..The nature of these potential interactions is discussed in the context of proximal-distal growth and patterning. ..
- Yang Y, Guillot P, Boyd Y, Lyon M, McMahon A. Evidence that preaxial polydactyly in the Doublefoot mutant is due to ectopic Indian Hedgehog signaling. Development. 1998;125:3123-32 pubmed..the ectopic activation of several genes associated with anterior-posterior and proximal-distal patterning (Fgf4, Hoxd13, Bmp2)...
- Yamaguchi T, Bradley A, McMahon A, Jones S. A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development. 1999;126:1211-23 pubmed..The reduced number of proliferating cells in both the progress zone and the primitive streak mesoderm suggests that one function of Wnt5a is to regulate the proliferation of progenitor cells. ..
- 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. ..
- Kondo T, Zakany J, Duboule D. Control of colinearity in AbdB genes of the mouse HoxD complex. Mol Cell. 1998;1:289-300 pubmed
- 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. ..
- Zakany J, Kmita M, Duboule D. A dual role for Hox genes in limb anterior-posterior asymmetry. Science. 2004;304:1669-72 pubmed..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...
- Zuniga A, Quillet R, Perrin Schmitt F, Zeller R. Mouse Twist is required for fibroblast growth factor-mediated epithelial-mesenchymal signalling and cell survival during limb morphogenesis. Mech Dev. 2002;114:51-9 pubmed..Finally, Twist function, most likely by regulating FGF signalling, is required for cell survival as apoptotic cells are detected in posterior and distal limb bud mesenchyme. ..
- 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. ..
- Gonzalez F, Duboule D, Spitz F. Transgenic analysis of Hoxd gene regulation during digit development. Dev Biol. 2007;306:847-59 pubmed..Based on DNA sequence conservation and transgenic assays, we discuss the functions of these regulatory regions as well as a potential evolutionary scheme accounting for their emergence along with the evolution of tetrapod limbs. ..
- 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. ..
- Seifert A, Yamaguchi T, Cohn M. Functional and phylogenetic analysis shows that Fgf8 is a marker of genital induction in mammals but is not required for external genital development. Development. 2009;136:2643-51 pubmed publisher..We propose that induction of external genitalia involves an epithelial-epithelial interaction at the cloacal membrane, and suggest that the cloacal ectoderm may be the source of the genital initiation signal...
- Warot X, Fromental Ramain C, Fraulob V, Chambon P, Dolle P. Gene dosage-dependent effects of the Hoxa-13 and Hoxd-13 mutations on morphogenesis of the terminal parts of the digestive and urogenital tracts. Development. 1997;124:4781-91 pubmed
- 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. ..
- Delpretti S, Zakany J, Duboule D. A function for all posterior Hoxd genes during digit development?. Dev Dyn. 2012;241:792-802 pubmed publisherFour posterior Hoxd genes, from Hoxd13 to Hoxd10, are collectively regulated during the development of tetrapod digits...
- 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. ..
- Cobb J, Duboule D. Comparative analysis of genes downstream of the Hoxd cluster in developing digits and external genitalia. Development. 2005;132:3055-67 pubmed..e. the digits and the penis/clitoris. ..
- te Welscher P, Zuniga A, Kuijper S, Drenth T, Goedemans H, Meijlink F, et al. Progression of vertebrate limb development through SHH-mediated counteraction of GLI3. Science. 2002;298:827-30 pubmed..Our genetic analysis indicates that SHH signaling counteracts GLI3-mediated repression of key regulator genes, cell survival, and distal progression of limb bud development. ..