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Gene Review

Hoxd13  -  homeobox D13

Mus musculus

Synonyms: Homeobox protein Hox-4.8, Homeobox protein Hox-D13, Hox-4.8, spdh
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Disease relevance of Hoxd13


High impact information on Hoxd13

  • The hypodactyly limb phenotype is similar to that of Hoxd13-deficient mice in sharing defects along multiple axes and alterations in cartilage maturation; however, the overall effects on digital arch formation are more severe in Hd/Hd mice [3].
  • Using the approach of gene disruption via homologous recombination in embryonic stem cells, we have assessed the function of the last gene of the complex, Hoxd-13 [4].
  • Using embryonic stem (ES) cells and a site-specific recombination system (loxP/Cre), we have induced a deficiency that eliminates the products of the Hoxd-13, Hoxd-12 and Hoxd-11 genes simultaneously [5].
  • Mice mutant for the Hoxd-13 gene have an important delay in morphogenesis owing to reduced proliferation [6].
  • Furthermore, the transgene induced a transient ectopic activation of the neighboring Hoxd13 gene, without affecting other genes of the complex [7].

Biological context of Hoxd13


Anatomical context of Hoxd13

  • Interestingly, re-expression of Hoxd13 occurs at late stages in the distal mesoderm of ozd leg buds, correlating with formation of digit 1 [12].
  • Similarly, in mice with disruptions of both Hoxa13 and Hoxd13, development of the forelimb and hindlimb autopod is severely curtailed [13].
  • Three of these genes, Hoxd11, Hoxd12, and Hoxd13, act synergistically to pattern the hindlimb autopod [14].
  • Expression of Hoxd13 was unaffected in Hoxa13-/- mice, but its domain was reduced at the anterior and posterior margins of the autopod in Hoxa13Hd/Hd limb buds [15].
  • 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 [1].

Associations of Hoxd13 with chemical compounds

  • The new mutation, named synpolydactyly homolog (spdh), is a 21 bp in-frame duplication within a polyalanine-encoding region at the 5'-end of the Hoxd13 coding sequence [16].
  • There is a close relationship, both temporal and spatial, between the activation of the Bmp-2 and Hoxd-13 genes in response to retinoic acid and polarizing region grafts, suggesting that expression of the two genes might be linked [17].
  • We identify retinaldehyde dehydrogenase 2 (Raldh2), the rate-limiting enzyme for retinoic acid (RA) synthesis in the limb, as a direct Hoxd13 target and show decreased RA production in limbs from Spdh/Spdh mice [18].

Regulatory relationships of Hoxd13


Other interactions of Hoxd13

  • The observations that Hoxd-12 and Hoxd-13 expression patterns were extended anteriorly provide a molecular basis for the posterior transformation of the anterior digit [20].
  • The presence of distal autopod elements is consistent with weak expression of Hoxd13 in Shh(-/-) hindlimbs [21].
  • 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 [22].
  • The analysis of these various genetic configurations revealed the important function of Evx-2 during the development of the autopod as well as its genetic interaction with Hoxd-13 [23].
  • We found that Hoxa-13 and Hoxd-13, which are members of the Abd-B subfamily of Hox genes and are crucial for the autopod development of the limb, stimulate transcription from the Bmp-4 promoter [24].

Analytical, diagnostic and therapeutic context of Hoxd13


  1. The synpolydactyly homolog (spdh) mutation in the mouse -- a defect in patterning and growth of limb cartilage elements. Albrecht, A.N., Schwabe, G.C., Stricker, S., Böddrich, A., Wanker, E.E., Mundlos, S. Mech. Dev. (2002) [Pubmed]
  2. Male accessory sex organ morphogenesis is altered by loss of function of Hoxd-13. Podlasek, C.A., Duboule, D., Bushman, W. Dev. Dyn. (1997) [Pubmed]
  3. The molecular basis of hypodactyly (Hd): a deletion in Hoxa 13 leads to arrest of digital arch formation. Mortlock, D.P., Post, L.C., Innis, J.W. Nat. Genet. (1996) [Pubmed]
  4. Disruption of the Hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs. Dollé, P., Dierich, A., LeMeur, M., Schimmang, T., Schuhbaur, B., Chambon, P., Duboule, D. Cell (1993) [Pubmed]
  5. Synpolydactyly in mice with a targeted deficiency in the HoxD complex. Zákány, J., Duboule, D. Nature (1996) [Pubmed]
  6. Hox gene expression in teleost fins and the origin of vertebrate digits. Sordino, P., van der Hoeven, F., Duboule, D. Nature (1995) [Pubmed]
  7. Mechanisms of Hox gene colinearity: transposition of the anterior Hoxb1 gene into the posterior HoxD complex. Kmita, M., van Der Hoeven, F., Zákány, J., Krumlauf, R., Duboule, D. Genes Dev. (2000) [Pubmed]
  8. The limb deformity mutation disrupts the SHH/FGF-4 feedback loop and regulation of 5' HoxD genes during limb pattern formation. Haramis, A.G., Brown, J.M., Zeller, R. Development (1995) [Pubmed]
  9. Suppression of polydactyly of the Gli3 mutant (extra toes) by deltaEF1 homozygous mutation. Moribe, H., Takagi, T., Kondoh, H., Higashi, Y. Dev. Growth Differ. (2000) [Pubmed]
  10. All for one and one for all: condensations and the initiation of skeletal development. Hall, B.K., Miyake, T. Bioessays (2000) [Pubmed]
  11. Effects of all-trans-retinoic acid on skeletal pattern, 5'HoxD gene expression, and RAR beta 2/beta 4 promoter activity in embryonic mouse limbs. Wood, H.B., Ward, S.J., Morriss-Kay, G.M. Dev. Genet. (1996) [Pubmed]
  12. The chick oligozeugodactyly (ozd) mutant lacks sonic hedgehog function in the limb. Ros, M.A., Dahn, R.D., Fernandez-Teran, M., Rashka, K., Caruccio, N.C., Hasso, S.M., Bitgood, J.J., Lancman, J.J., Fallon, J.F. Development (2003) [Pubmed]
  13. Multiple roles of Hoxa11 and Hoxd11 in the formation of the mammalian forelimb zeugopod. Boulet, A.M., Capecchi, M.R. Development (2004) [Pubmed]
  14. Targeted disruption of Hoxd9 and Hoxd10 alters locomotor behavior, vertebral identity, and peripheral nervous system development. de la Cruz, C.C., Der-Avakian, A., Spyropoulos, D.D., Tieu, D.D., Carpenter, E.M. Dev. Biol. (1999) [Pubmed]
  15. Altered Hox expression and increased cell death distinguish Hypodactyly from Hoxa13 null mice. Post, L.C., Innis, J.W. Int. J. Dev. Biol. (1999) [Pubmed]
  16. A new spontaneous mouse mutation of Hoxd13 with a polyalanine expansion and phenotype similar to human synpolydactyly. Johnson, K.R., Sweet, H.O., Donahue, L.R., Ward-Bailey, P., Bronson, R.T., Davisson, M.T. Hum. Mol. Genet. (1998) [Pubmed]
  17. Bone morphogenetic proteins and a signalling pathway that controls patterning in the developing chick limb. Francis, P.H., Richardson, M.K., Brickell, P.M., Tickle, C. Development (1994) [Pubmed]
  18. Mutant Hoxd13 induces extra digits in a mouse model of synpolydactyly directly and by decreasing retinoic acid synthesis. Kuss, P., Villavicencio-Lorini, P., Witte, F., Klose, J., Albrecht, A.N., Seemann, P., Hecht, J., Mundlos, S. J. Clin. Invest. (2009) [Pubmed]
  19. 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. Dollé, P., Izpisúa-Belmonte, J.C., Boncinelli, E., Duboule, D. Mech. Dev. (1991) [Pubmed]
  20. Targeted misexpression of constitutively active BMP receptor-IB causes bifurcation, duplication, and posterior transformation of digit in mouse limb. Zhang, Z., Yu, X., Zhang, Y., Geronimo, B., Lovlie, A., Fromm, S.H., Chen, Y. Dev. Biol. (2000) [Pubmed]
  21. Some distal limb structures develop in mice lacking Sonic hedgehog signaling. Kraus, P., Fraidenraich, D., Loomis, C.A. Mech. Dev. (2001) [Pubmed]
  22. An enhancer-titration effect induces digit-specific regulatory alleles of the HoxD cluster. Monge, I., Kondo, T., Duboule, D. Dev. Biol. (2003) [Pubmed]
  23. Function of the Evx-2 gene in the morphogenesis of vertebrate limbs. Hérault, Y., Hraba-Renevey, S., van der Hoeven, F., Duboule, D. EMBO J. (1996) [Pubmed]
  24. Hox proteins functionally cooperate with the GC box-binding protein system through distinct domains. Suzuki, M., Ueno, N., Kuroiwa, A. J. Biol. Chem. (2003) [Pubmed]
  25. Polarizing activity, Sonic hedgehog, and tooth development in embryonic and postnatal mouse. Koyama, E., Yamaai, T., Iseki, S., Ohuchi, H., Nohno, T., Yoshioka, H., Hayashi, Y., Leatherman, J.L., Golden, E.B., Noji, S., Pacifici, M. Dev. Dyn. (1996) [Pubmed]
  26. Gene dosage-dependent effects of the Hoxa-13 and Hoxd-13 mutations on morphogenesis of the terminal parts of the digestive and urogenital tracts. Warot, X., Fromental-Ramain, C., Fraulob, V., Chambon, P., Dollé, P. Development (1997) [Pubmed]
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