Gene Symbol: Hoxd4
Description: homeobox D4
Alias: 6030436D05Rik, Hox-4.2, Hox-5.1, homeobox protein Hox-D4, homeo box D4, homeobox protein Hox-4.2, homeobox protein Hox-5.1
Species: mouse
Products:     Hoxd4

Top Publications

  1. Carver E, Issel Tarver L, Rine J, Olsen A, Stubbs L. Location of mouse and human genes corresponding to conserved canine olfactory receptor gene subfamilies. Mamm Genome. 1998;9:349-54 pubmed
    ..Combined with recently published studies, these data link the four conserved olfactory gene subfamilies to homologous regions of the human, dog, and mouse genomes. ..
  2. Gould A, Morrison A, Sproat G, White R, Krumlauf R. Positive cross-regulation and enhancer sharing: two mechanisms for specifying overlapping Hox expression patterns. Genes Dev. 1997;11:900-13 pubmed
    ..CR3 mediates transcriptional activation by multiple Hox genes, including Hoxb4, Hoxd4, and Hoxb5 but not Hoxb1...
  3. McKay I, Muchamore I, Krumlauf R, Maden M, Lumsden A, Lewis J. The kreisler mouse: a hindbrain segmentation mutant that lacks two rhombomeres. Development. 1994;120:2199-211 pubmed
    ..An interpretation is that the cells that would normally become specified at an early stage as r5 and r6 adopt an r4 character instead, producing an excess of r4 cells that is disposed of subsequently by cell death. ..
  4. Izpisua Belmonte J, Dolle P, Renucci A, Zappavigna V, Falkenstein H, Duboule D. Primary structure and embryonic expression pattern of the mouse Hox-4.3 homeobox gene. Development. 1990;110:733-45 pubmed
    ..Like other genes of the HOX-4(5) complex, Hox-4.3 is expressed in developing limbs and gonads, suggesting that 'cluster specificity' could be a feature of the HOX network. ..
  5. Folberg A, Kovács E, Featherstone M. Characterization and retinoic acid responsiveness of the murine Hoxd4 transcription unit. J Biol Chem. 1997;272:29151-7 pubmed
    We have characterized the transcription unit of a murine Hox gene in the fourth paralogous group, Hoxd4. We have identified two Hoxd4 transcription start sites by S1 analysis. The upstream promoter (P2) is 5...
  6. Morrison A, Ariza McNaughton L, Gould A, Featherstone M, Krumlauf R. HOXD4 and regulation of the group 4 paralog genes. Development. 1997;124:3135-46 pubmed
    ..In this study, we have used transgenic analysis of the human HOXD4 locus to identify one neural and two mesodermal 3' enhancers that are capable of mediating the proper anterior ..
  7. Nolte C, Amores A, Nagy Kovács E, Postlethwait J, Featherstone M. The role of a retinoic acid response element in establishing the anterior neural expression border of Hoxd4 transgenes. Mech Dev. 2003;120:325-35 pubmed
    The zebrafish hoxd4a locus was compared to its murine ortholog, Hoxd4. The sequence of regulatory elements, including a DR5 type retinoic acid response element (RARE) required for Hoxd4 neural enhancer activity, are highly conserved...
  8. Duboule D, Dolle P. The structural and functional organization of the murine HOX gene family resembles that of Drosophila homeotic genes. EMBO J. 1989;8:1497-505 pubmed
    ..Thus, very different body plans might be achieved, both in insects and vertebrates, by evolutionarily conserved gene networks possibly displaying similar regulatory interactions. ..
  9. Horan G, Kovács E, Behringer R, Featherstone M. Mutations in paralogous Hox genes result in overlapping homeotic transformations of the axial skeleton: evidence for unique and redundant function. Dev Biol. 1995;169:359-72 pubmed
    ..The phenotypic similarities and differences between Hoxd-4 and previously reported Hoxa-4 and Hoxb-4 mutant mice suggest that Hox gene paralogs have both redundant and unique functions. ..

More Information


  1. Gaunt S, Krumlauf R, Duboule D. Mouse homeo-genes within a subfamily, Hox-1.4, -2.6 and -5.1, display similar anteroposterior domains of expression in the embryo, but show stage- and tissue-dependent differences in their regulation. Development. 1989;107:131-41 pubmed
    ..We also propose how our new findings may help to explain any selective advantage to the vertebrates of homeo-gene duplication to form subfamilies. ..
  2. 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. ..
  3. Horan G, Ramirez Solis R, Featherstone M, Wolgemuth D, Bradley A, Behringer R. Compound mutants for the paralogous hoxa-4, hoxb-4, and hoxd-4 genes show more complete homeotic transformations and a dose-dependent increase in the number of vertebrae transformed. Genes Dev. 1995;9:1667-77 pubmed
  4. Zhang F, Nagy Kovács E, Featherstone M. Murine hoxd4 expression in the CNS requires multiple elements including a retinoic acid response element. Mech Dev. 2000;96:79-89 pubmed
    We have identified a retinoic acid response element (RARE) within a neural enhancer located 3' to the Hoxd4 gene...
  5. Serpente P, Tümpel S, Ghyselinck N, Niederreither K, Wiedemann L, Dolle P, et al. Direct crossregulation between retinoic acid receptor {beta} and Hox genes during hindbrain segmentation. Development. 2005;132:503-13 pubmed
    ..that regresses until, at later stages, it is stably maintained at the r6/r7 boundary by inputs from Hoxb4 and Hoxd4. Separate RA- and Hox-responsive enhancers mediate the two phases of Rarb expression: a regulatory mechanism ..
  6. Tarchini B, Duboule D. Control of Hoxd genes' collinearity during early limb development. Dev Cell. 2006;10:93-103 pubmed
  7. Nolte C, Rastegar M, Amores A, Bouchard M, Grote D, Maas R, et al. Stereospecificity and PAX6 function direct Hoxd4 neural enhancer activity along the antero-posterior axis. Dev Biol. 2006;299:582-93 pubmed
    ..We have reported on a neural enhancer of Hoxd4 that directs expression in the CNS with the correct anterior border in the hindbrain...
  8. Featherstone M, Baron A, Gaunt S, Mattei M, Duboule D. Hox-5.1 defines a homeobox-containing gene locus on mouse chromosome 2. Proc Natl Acad Sci U S A. 1988;85:4760-4 pubmed
    ..In situ hybridization to sections from whole mouse embryos revealed Hox-5.1 expression in spinal cord and prevertebrae. ..
  9. Rastegar M, Kobrossy L, Kovacs E, Rambaldi I, Featherstone M. Sequential histone modifications at Hoxd4 regulatory regions distinguish anterior from posterior embryonic compartments. Mol Cell Biol. 2004;24:8090-103 pubmed
    ..We used chromatin immunoprecipitation to detect chromatin changes at the Hoxd4 locus during neurogenesis in P19 cells and embryonic day 8.0 (E8.0) and E10.5 mouse embryos...
  10. Tschopp P, Tarchini B, Spitz F, Zakany J, Duboule D. Uncoupling time and space in the collinear regulation of Hox genes. PLoS Genet. 2009;5:e1000398 pubmed publisher
    ..We discuss the potential functions and evolutionary origins of these mechanisms, as well as their relationship with similar processes at work during limb development. ..
  11. 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. ..
  12. 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. ..
  13. 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
  14. Siracusa L, Alvord W, Bickmore W, Jenkins N, Copeland N. Interspecific backcross mice show sex-specific differences in allelic inheritance. Genetics. 1991;128:813-21 pubmed
    ..These studies provide evidence for sex-specific differences in allelic inheritance for chromosome 2 and suggest biological explanations for this form of transmission distortion. ..
  15. Popperl H, Featherstone M. Identification of a retinoic acid response element upstream of the murine Hox-4.2 gene. Mol Cell Biol. 1993;13:257-65 pubmed
    ..In addition, the response to RA could be inhibited by expressing a dominant negative form of RAR alpha in transfected P19 EC cells. These results suggested that Hox-4.2 is a target for RAR-mediated regulation by RA. ..
  16. Isono K, Mizutani Koseki Y, Komori T, Schmidt Zachmann M, Koseki H. Mammalian polycomb-mediated repression of Hox genes requires the essential spliceosomal protein Sf3b1. Genes Dev. 2005;19:536-41 pubmed
    ..Importantly, the levels of Sf3b1 in PcG complexes were decreased in Sf3b1-heterozygous embryos. These findings suggest that Sf3b1-PcG protein interaction is essential for true PcG-mediated repression of Hox genes. ..
  17. Murashima A, Akita H, Okazawa M, Kishigami S, Nakagata N, Nishinakamura R, et al. Midline-derived Shh regulates mesonephric tubule formation through the paraxial mesoderm. Dev Biol. 2014;386:216-26 pubmed publisher
    ..These data demonstrate the essential role of midline-derived Shh in local tissue morphogenesis and differentiation. ..
  18. Rouquier S, Stubbs L, Gaillard Sanchez I, Giorgi D. Sequence and chromosomal localization of the mouse ortholog of the human olfactory receptor gene 912-93. Mamm Genome. 1999;10:1172-4 pubmed
  19. Ikeya M, Takada S. Wnt-3a is required for somite specification along the anteroposterior axis of the mouse embryo and for regulation of cdx-1 expression. Mech Dev. 2001;103:27-33 pubmed
    ..These results indicate that Wnt-3a is necessary for correct anteroposterior patterning of vertebra, and that cdx-1 may be one of the mediator genes of Wnt-3a signaling in this process. ..
  20. Guris D, Duester G, Papaioannou V, Imamoto A. Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome. Dev Cell. 2006;10:81-92 pubmed
    ..Thus, we suggest that del22q11 is a contiguous gene syndrome involving dose-sensitive interaction of CRKL and TBX1 and locally aberrant RA signaling. ..
  21. Pilon N, Oh K, Sylvestre J, Savory J, Lohnes D. Wnt signaling is a key mediator of Cdx1 expression in vivo. Development. 2007;134:2315-23 pubmed
    ..As Wnt signaling is implicated in somitogenesis upstream of the Notch pathway, it is conceivable that Cdx1 might play a role in this process. However, none of the Notch pathway genes assessed was overtly affected. ..
  22. Duboule D, Boncinelli E, DeRobertis E, Featherstone M, Lonai P, Oliver G, et al. An update of mouse and human HOX gene nomenclature. Genomics. 1990;7:458-9 pubmed
  23. Dolle P, Izpisua Belmonte J, Boncinelli E, Duboule D. The Hox-4.8 gene is localized at the 5' extremity of the Hox-4 complex and is expressed in the most posterior parts of the body during development. Mech Dev. 1991;36:3-13 pubmed
    ..8 is expressed in more posterodistal regions than those of its neighbour Hox-4.7. Hence, Hox-4.8 expression appears to be related to the last significant phenotypic changes towards the extremities of the embryonic body and limb axes. ..
  24. Nazarali A, Kim Y, Nirenberg M. Hox-1.11 and Hox-4.9 homeobox genes. Proc Natl Acad Sci U S A. 1992;89:2883-7 pubmed
    ..3 and Hox-4.2 genomic DNA revealed some differences in nucleotide sequences and in the deduced homeodomain amino acid sequences compared with the sequences that have been reported. ..
  25. Zacchetti G, Duboule D, Zakany J. Hox gene function in vertebrate gut morphogenesis: the case of the caecum. Development. 2007;134:3967-73 pubmed
    ..These results illuminate components of the genetic cascade necessary for the emergence of this gut segment, crucial for many vertebrates. ..
  26. Tschopp P, Christen A, Duboule D. Bimodal control of Hoxd gene transcription in the spinal cord defines two regulatory subclusters. Development. 2012;139:929-39 pubmed publisher
  27. Schep R, Necsulea A, Rodríguez Carballo E, Guerreiro I, Andrey G, Nguyen Huynh T, et al. Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape. Proc Natl Acad Sci U S A. 2016;113:E7720-E7729 pubmed
    ..We propose that Hoxd gene regulation in embryonic MBs evolved by hijacking a preexisting regulatory landscape that was already at work before the emergence of mammals in structures such as the limbs or the intestinal tract. ..
  28. Niederreither K, Vermot J, Schuhbaur B, Chambon P, Dolle P. Retinoic acid synthesis and hindbrain patterning in the mouse embryo. Development. 2000;127:75-85 pubmed
    ..We conclude that RA produced by the embryo is required to generate posterior cell fates in the developing mouse hindbrain, its absence leading to an abnormal r3 (and, to a lesser extent, r4) identity of the caudal hindbrain cells. ..
  29. Sadoul R, Featherstone M. Sequence analysis of the homeobox-containing exon of the murine Hox-4.3 homeogene. Biochim Biophys Acta. 1991;1089:259-61 pubmed
    ..3 gene. No other homeobox sequences were detected in this screen suggesting that the HOX-4 complex lacks paralogous genes represented in the equivalent regions of other HOX loci. ..
  30. Siracusa L, Silan C, Justice M, Mercer J, Bauskin A, Ben Neriah Y, et al. A molecular genetic linkage map of mouse chromosome 2. Genomics. 1990;6:491-504 pubmed
    ..Comparisons between the mouse and the human genomes indicate that mouse chromosome 2 contains regions homologous to at least six human chromosomes. Mouse models for human diseases are discussed. ..
  31. Bedford M, Arman E, Orr Urtreger A, Lonai P. Analysis of the Hoxd-3 gene: structure and localization of its sense and natural antisense transcripts. DNA Cell Biol. 1995;14:295-304 pubmed
    ..5 days p.c. in cDNA libraries. At 12.5 days p.c., sense and antisense transcripts colocalized in the liver. The possible role of antisense homeobox transcripts during liver and the hematopoietic development is discussed. ..
  32. Dupé V, Ghyselinck N, Wendling O, Chambon P, Mark M. Key roles of retinoic acid receptors alpha and beta in the patterning of the caudal hindbrain, pharyngeal arches and otocyst in the mouse. Development. 1999;126:5051-9 pubmed
  33. Folberg A, Kovács E, Huang H, Houle M, Lohnes D, Featherstone M. Hoxd4 and Rarg interact synergistically in the specification of the cervical vertebrae. Mech Dev. 1999;89:65-74 pubmed
    We show that, relative to single null mutants, mice bearing mutations in both Hoxd4 and Rarg display malformations of the basioccipital bone, and first (C1) and second cervical vertebrae (C2) at increased penetrance and expressivity, ..
  34. Prin F, Serpente P, Itasaki N, Gould A. Hox proteins drive cell segregation and non-autonomous apical remodelling during hindbrain segmentation. Development. 2014;141:1492-502 pubmed publisher
    ..Loss-of-function mutants and ectopic expression assays reveal that Hoxb4 and its paralogue Hoxd4 are necessary and sufficient for cell segregation, and for the most caudal rhombomere boundary (r6/r7)...
  35. Core N, Bel S, Gaunt S, Aurrand Lions M, Pearce J, Fisher A, et al. Altered cellular proliferation and mesoderm patterning in Polycomb-M33-deficient mice. Development. 1997;124:721-9 pubmed
    ..5, leading to the hypothesis that, during development, the M33 gene might play a role in defining access to retinoic acid response elements localised in the regulatory regions of several Hox genes. ..
  36. Lufkin T, Mark M, Hart C, Dolle P, LeMeur M, Chambon P. Homeotic transformation of the occipital bones of the skull by ectopic expression of a homeobox gene. Nature. 1992;359:835-41 pubmed
    ..2. These results are similar to the homeotic posteriorization phenomenon generated in Drosophila by ectopic expression of genes of the homeotic complex HOM-C (refs 7-10; reviewed in ref. 3). ..
  37. Delpretti S, Montavon T, Leleu M, Joye E, Tzika A, Milinkovitch M, et al. Multiple enhancers regulate Hoxd genes and the Hotdog LncRNA during cecum budding. Cell Rep. 2013;5:137-50 pubmed publisher
    ..In this context, we discuss the implementation of a common "budding toolkit" between the cecum and the limbs. ..
  38. Gaunt S, Strachan L. Forward spreading in the establishment of a vertebrate Hox expression boundary: the expression domain separates into anterior and posterior zones, and the spread occurs across implanted glass barriers. Dev Dyn. 1994;199:229-40 pubmed
    ..We suggest that the posterior zone marks the source of a morphogen which is the primary activator of Hox gene expression, and we discuss possible models for the mechanism of forward spreading in expression. ..
  39. Akasaka T, van Lohuizen M, van der Lugt N, Mizutani Koseki Y, Kanno M, Taniguchi M, et al. Mice doubly deficient for the Polycomb Group genes Mel18 and Bmi1 reveal synergy and requirement for maintenance but not initiation of Hox gene expression. Development. 2001;128:1587-97 pubmed
    ..Furthermore, we show an unexpected requirement for Mel18 and Bmi1 gene products to maintain stable expression of Hox cluster genes in regions caudal to the prospective anterior expression boundaries during subsequent development. ..
  40. Lonai P, Arman E, Czosnek H, Ruddle F, Blatt C. New murine homeoboxes: structure, chromosomal assignment, and differential expression in adult erythropoiesis. DNA. 1987;6:409-18 pubmed
    ..All four homeoboxes are expressed in the mouse embryo. Of special interest is the expression of mh19, a 4.2-kb transcript of which appears to be connected to the induced differentiation of Friend erythroleukemia cells. ..
  41. Kruger C, Kappen C. Expression of cartilage developmental genes in Hoxc8- and Hoxd4-transgenic mice. PLoS ONE. 2010;5:e8978 pubmed publisher
    ..Overexpression of the homeobox transcription factors Hoxc8 and Hoxd4 causes severe cartilage defects due to delay in cartilage maturation...
  42. van den Akker E, Forlani S, Chawengsaksophak K, de Graaff W, Beck F, Meyer B, et al. Cdx1 and Cdx2 have overlapping functions in anteroposterior patterning and posterior axis elongation. Development. 2002;129:2181-93 pubmed
    ..The function of Cdx genes in morphogenetic processes during gastrulation and tail bud extension, and their relationship with the Hox genes are discussed in the light of available data in Amphioxus, C. elegans, Drosophila and mice. ..
  43. Popperl H, Featherstone M. An autoregulatory element of the murine Hox-4.2 gene. EMBO J. 1992;11:3673-80 pubmed
    ..2 gene (HOX4B) which has been shown to display spatial enhancer activity in mice and flies. These findings suggest a conserved autoregulatory mechanism for the control of Hox-4.2 expression. ..
  44. Sheth R, Bastida M, Kmita M, Ros M. "Self-regulation," a new facet of Hox genes' function. Dev Dyn. 2014;243:182-91 pubmed publisher
    ..e., HOX controlling the establishment of the ultimate HOX code. ..
  45. Minoux M, Antonarakis G, Kmita M, Duboule D, Rijli F. Rostral and caudal pharyngeal arches share a common neural crest ground pattern. Development. 2009;136:637-45 pubmed publisher
    ..These results provide insights into how facial and throat structures are assembled during development, and have implications for the evolution of the pharyngeal region of the vertebrate head. ..
  46. Trokovic N, Trokovic R, Mai P, Partanen J. Fgfr1 regulates patterning of the pharyngeal region. Genes Dev. 2003;17:141-53 pubmed
    ..Our results indicate that Fgfr1 patterns the pharyngeal region to create a permissive environment for neural crest cell migration. ..
  47. Kobrossy L, Rastegar M, Featherstone M. Interplay between chromatin and trans-acting factors regulating the Hoxd4 promoter during neural differentiation. J Biol Chem. 2006;281:25926-39 pubmed
    ..In this study, we identified components of the Hoxd4 P1 promoter directing expression in neurally differentiating retinoic acid-treated P19 cells...
  48. Terranova R, Agherbi H, Boned A, Méresse S, Djabali M. Histone and DNA methylation defects at Hox genes in mice expressing a SET domain-truncated form of Mll. Proc Natl Acad Sci U S A. 2006;103:6629-34 pubmed
    ..These observations provide previously undescribed evidence for the in vivo relationship and SET domain dependence between histone methylation and DNA methylation on MLL target genes during embryonic development. ..
  49. Duboule D. The function of Hox genes in the morphogenesis of the vertebrate limb. Ann Genet. 1993;36:24-9 pubmed
    ..The asymmetric distribution of the Hox transcript during limb development likely reflects the final limb asymmetry. ..
  50. Xu X, Li C, Takahashi K, Slavkin H, Shum L, Deng C. Murine fibroblast growth factor receptor 1alpha isoforms mediate node regression and are essential for posterior mesoderm development. Dev Biol. 1999;208:293-306 pubmed
    ..These data demonstrate that FGF/FGFR1alpha signals are posteriorizing factors that control node regression and posterior embryonic development. ..
  51. Phua S, Sivakamasundari V, Shao Y, Cai X, Zhang L, Lufkin T, et al. Nuclear accumulation of an uncapped RNA produced by Drosha cleavage of a transcript encoding miR-10b and HOXD4. PLoS ONE. 2011;6:e25689 pubmed publisher
    ..The murine Hoxd4 gene has been proposed to harbour two promoters, an upstream promoter P2, and a downstream promoter P1, that lie 5...
  52. Kappen C, Yaworsky P, Muller Y, Salbaum J. Transgenic studies on homeobox genes in nervous system development: spina bifida in Isl1 transgenic mice. Transgenic Res. 2013;22:343-58 pubmed publisher
    ..Transgenic expression of Hoxc8 did not result in gross abnormalities, while a Hoxd4 transgene caused death shortly after birth...
  53. Yasunaga S, Ohtsubo M, Ohno Y, Saeki K, Kurogi T, Tanaka Okamoto M, et al. Scmh1 has E3 ubiquitin ligase activity for geminin and histone H2A and regulates geminin stability directly or indirectly via transcriptional repression of Hoxa9 and Hoxb4. Mol Cell Biol. 2013;33:644-60 pubmed publisher
    ..These findings suggest that PcG and a subset of Hox genes compose a homeostatic regulatory system for determining expression level of geminin. ..