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Gene Review

Hoxa13  -  homeobox A13

Mus musculus

Synonyms: Hd, Homeobox protein Hox-1.10, Homeobox protein Hox-A13, Hox-1.10
 
 
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Disease relevance of Hoxa13

  • In males, one of the most common GU malformations associated with loss of Hoxa13 function is hypospadia, a condition defined by the poor growth and closure of the urethra and glans penis [1].
  • Hoxa-13(-/-) mutant fetuses show agenesis of the caudal portion of the Müllerian ducts, lack of development of the presumptive urinary bladder and premature stenosis of the umbilical arteries, which could account for the lethality of this mutation at mid-gestational stages [2].
 

High impact information on Hoxa13

  • We have determined the structure of the Hoxa13 gene and describe a 50-base pair deletion in the first exon of the Hd allele that probably arose from unequal recombination or misalignment between triplet repeats [3].
  • Genetic studies have shown that Igk-Ef2 locus is closely linked to Igk-Ef1 and Hd loci on Chromosome 6, indicating that it is also closely linked to Ly-3 [4].
  • Mutant limb buds had normal steady-state Hoxa13 RNA expression, normal mRNA splicing and reduced levels of steady-state protein [5].
  • Similarly, in mice with disruptions of both Hoxa13 and Hoxd13, development of the forelimb and hindlimb autopod is severely curtailed [6].
  • Mice mutant for Hoxa13 also exhibit changes in androgen receptor expression, providing a developmental link between Hoxa13-associated hypospadias and those produced by antagonists to androgen signaling [1].
 

Biological context of Hoxa13

  • Hypodactyly (Hoxa13Hd) mice have a small deletion within the coding sequence of Hoxa13 and a limb phenotype that is more severe than that of mice with an engineered null allele of Hoxa13 [7].
  • Altered Hox expression and increased cell death distinguish Hypodactyly from Hoxa13 null mice [7].
  • The semidominant mouse mutation hypodactyly (Hd), caused by a deletion within the Hoxa13 gene, results in reduced digits; heterozygotes lack digit I in the hindlimb and homozygotes have only one digit on each limb [8].
  • These results suggest that an important role for Hoxa13 during limb and UA development is to regulate genes whose products are required for mesenchymal cell adhesion, sorting and boundary formation [9].
  • In this paper, we characterize the Hoxa13 transcription initiation site in limbs and determine the initiator methionine of HOXA13 [10].
 

Anatomical context of Hoxa13

  • By examining early signaling in the developing mouse genital tubercle, we show that Hoxa13 is essential for normal expression of Fgf8 and Bmp7 in the urethral plate epithelium [1].
  • These results showthat Hoxa13Hd has a negative effect on the survival of the mesenchyme in the autopod, unlike the Hoxa13 null mutation, that cannot be explained by a failure of the AER to express Fgfs [7].
  • A dramatic increase in cell death was observed in limb bud mesenchyme of Hoxa13Hd/Hd mice as early as E11.5 but not in mice homozygous for the null allele [7].
  • EphA7 and EphA4 expression were also decreased in the mesenchymal and endothelial cells that form the umbilical arteries in Hoxa13 mutant homozygous embryos [9].
  • The role of Hoxa-13 in postnatal morphogenesis of the male accessory sex organs was assessed by correlating the Hoxa-13 expression domain with phenotypic abnormalities in heterozygous Hypodactyly mutants [11].
 

Associations of Hoxa13 with chemical compounds

 

Physical interactions of Hoxa13

 

Regulatory relationships of Hoxa13

  • We demonstrate that Hoxa-13 is broadly expressed in the developing lower genitourinary tract and that the Hypodactyly mutation results in a specific phenotype characterized by decreased size and branching of the dorsolateral and ventral prostate and abnormal seminal vesicle morphology [11].
 

Other interactions of Hoxa13

 

Analytical, diagnostic and therapeutic context of Hoxa13

  • Analysis of pro-adhesion molecules in the autopod of Hoxa13 mutants revealed a marked reduction in EphA7 expression in affected digits, as well as in micromass cell cultures prepared from mutant mesenchymal cells [9].
  • Expression differences in the HOXA13-expressing cells were confirmed for selected downstream genes using semi-quantitative RT-PCR, and in vivo coexpression with Hoxa13 in the limb interdigital mesenchyme was demonstrated for many [14].
  • Gene targeting experiments have shown that the murine Hoxa-13 and Hoxd-13 paralogous genes control skeletal patterning in the distal region of the developing limbs [2].

References

  1. Loss of Bmp7 and Fgf8 signaling in Hoxa13-mutant mice causes hypospadia. Morgan, E.A., Nguyen, S.B., Scott, V., Stadler, H.S. Development (2003) [Pubmed]
  2. 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]
  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. Ef2: a new LY-3-linked light-chain marker expressed in normal mouse serum immunoglobulin. Gibson, D.M., MacLean, S.J. J. Exp. Med. (1979) [Pubmed]
  5. Polyalanine expansion in HOXA13: three new affected families and the molecular consequences in a mouse model. Innis, J.W., Mortlock, D., Chen, Z., Ludwig, M., Williams, M.E., Williams, T.M., Doyle, C.D., Shao, Z., Glynn, M., Mikulic, D., Lehmann, K., Mundlos, S., Utsch, B. Hum. Mol. Genet. (2004) [Pubmed]
  6. Multiple roles of Hoxa11 and Hoxd11 in the formation of the mammalian forelimb zeugopod. Boulet, A.M., Capecchi, M.R. Development (2004) [Pubmed]
  7. 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]
  8. Shh, Fgf4 and Hoxd gene expression in the mouse limb mutant hypodactyly. Robertson, K.E., Tickle, C., Darling, S.M. Int. J. Dev. Biol. (1997) [Pubmed]
  9. Loss of Eph-receptor expression correlates with loss of cell adhesion and chondrogenic capacity in Hoxa13 mutant limbs. Stadler, H.S., Higgins, K.M., Capecchi, M.R. Development (2001) [Pubmed]
  10. Severe limb defects in Hypodactyly mice result from the expression of a novel, mutant HOXA13 protein. Post, L.C., Margulies, E.H., Kuo, A., Innis, J.W. Dev. Biol. (2000) [Pubmed]
  11. Hoxa-13 gene mutation results in abnormal seminal vesicle and prostate development. Podlasek, C.A., Clemens, J.Q., Bushman, W. J. Urol. (1999) [Pubmed]
  12. Hoxd13 and Hoxa13 directly control the expression of the EphA7 Ephrin tyrosine kinase receptor in developing limbs. Salsi, V., Zappavigna, V. J. Biol. Chem. (2006) [Pubmed]
  13. Orientation of the Hoxa complex and placement of the Hd locus distal to Hoxa2 on mouse chromosome 6. Innis, J.W., Darling, S.M., Kazen-Gillespie, K., Post, L.C., Mortlock, D.P., Yang, T. Mamm. Genome (1996) [Pubmed]
  14. Candidate downstream regulated genes of HOX group 13 transcription factors with and without monomeric DNA binding capability. Williams, T.M., Williams, M.E., Kuick, R., Misek, D., McDonagh, K., Hanash, S., Innis, J.W. Dev. Biol. (2005) [Pubmed]
  15. A mouse homeo box gene, Hox-1.5, and the morphological locus, Hd, map to within 1 cM on chromosome 6. Mock, B.A., D'Hoostelaere, L.A., Matthai, R., Huppi, K. Genetics (1987) [Pubmed]
 
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