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Hhex  -  hematopoietically expressed homeobox

Mus musculus

Synonyms: Hematopoietically-expressed homeobox protein Hhex, Hex, Hex1, Hhex-rs2, Homeobox protein HEX, ...
 
 
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Disease relevance of Hhex

  • To determine whether Hex misexpression results in the altered differentiation or neoplastic transformation of hematopoietic lineages, we have transplanted mice with bone marrow cells transduced with retrovirus containing the Hex coding region [1].
  • In particular, in the region of the foregut that gives rise to the liver, Hex expression is nuclear in the endodermal cells of the hepatic diverticulum, whereas expression is primarily cytoplasmic in cells lateral to the liver-forming region [2].
  • Tay-Sachs and Sandhoff diseases are autosomal recessive neurodegenerative diseases resulting from the inability to catabolize GM2 ganglioside by beta-hexosaminidase A (Hex A) due to mutations of the alpha subunit (Tay-Sachs disease) or beta subunit (Sandhoff disease) of Hex A [3].
  • Therapy for neurodegenerative lysosomal Tay-Sachs (TS) disease requires active hexosaminidase (Hex) A production in the central nervous system and an efficient therapeutic approach that can act faster than human disease progression [4].
  • We combined the efficacy of a non-replicating Herpes simplex vector encoding for the Hex A alpha-subunit (HSV-T0alphaHex) and the anatomic structure of the brain internal capsule to distribute the missing enzyme optimally [4].
 

High impact information on Hhex

  • In amphibians, Spemann's organizer, which is homologous to the node, partially overlaps with anterior endoderm cells expressing homologues of the AVE markers cerberus, Hex and Hesx1 [5].
  • Thus, to initiate cardiogenesis, Wnt antagonists act on endoderm to up-regulate Hex, which, in turn, controls production of a diffusible heart-inducing factor [6].
  • This novel function for Hex suggests an etiology for the cardiac malformations in Hex mutant mice and will make possible the isolation of factors that induce heart directly in the mesoderm [6].
  • Loss of Hex function blocks both endogenous heart development and ectopic heart induction by Dkk-1 [6].
  • Impaired B cell development and function in mice with a targeted disruption of the homeobox gene Hex [7].
 

Biological context of Hhex

 

Anatomical context of Hhex

  • Because Hhex is expressed in the developing blood islands at E7.0 in the endothelium of the developing vasculature and heart at E9.0-9.5, and in the ventral foregut endoderm at E8.5-9.0, it has been postulated to play a critical role in heart and vascular development [8].
  • In addition to differences in these progenitor populations, we also found that endothelial cells from the Hex(-/-) EBs showed enhanced proliferative potential compared with those from wild-type EBs [9].
  • Molecular analysis showed that Hex is expressed in mesoderm, in populations that contain BL-CFCs, and in blast cell colonies, the progeny of the BL-CFCs [9].
  • The homeobox gene Hex is expressed in multiple cell types during embryogenesis and is required for liver and monocyte development [10].
  • The Hex promoter region from nt -235/+22 conferred basal activity in both HepG2 and Cos cells, with the region from -103/+22 conferring liver-enriched activity [11].
 

Associations of Hhex with chemical compounds

  • A polyclonal antibody against a glutathione S:-transferase fusion protein containing the 76 COOH-terminal amino acids of Hex, a divergent homeobox gene, was raised in rabbits [2].
  • Up to 75% of the inactivation of Hex B was prevented by including the competitive inhibitor 2-acetamido-2-deoxy-D-glucono-1,5-lactone in the photoaffinity experiment [12].
  • The carbene precursor 3-azi-1-[([6-3H]-2-acetamido-2-deoxy-1-beta-D-galactopyranosyl)thi o -butane (also designated [3H]-1-ATB-GalNAc) has been used as a photoaffinity label for human lysosomal beta-hexosaminidase B (Hex B, EC 3.2.1.52) purified to apparent homogeneity from postmortal liver [12].
  • 4. Hexamethonium (Hex, 0.5 to 8 microM) inhibited the agonist-induced current and produced voltage-jump relaxations characterized by a rapid conductance increase and a slower conductance decrease [13].
  • To explain the extensive epididymal abnormalities in the Hexb-/- mice, we propose that substrates for Hex, such as testis-derived glycolipids, cannot be catabolized and accumulate in lysosomes, leading to epididymal dysfunction and abnormalities in the epididymal luminal environment that supports sperm maturation [14].
 

Physical interactions of Hhex

 

Regulatory relationships of Hhex

 

Other interactions of Hhex

  • A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels [8].
  • Ventral endodermal expression of Hex is not affected in Raldh2-/- embryos, indicating that liver specification is not dependent upon RA [19].
  • We hypothesized that putative HNF3beta and GATA-4 elements within the Hex promoter would confer liver-enriched expression [11].
  • Expression of the homeobox gene Hex (the earliest known marker of the A-P polarity and the prospective head organizer) was found to be missing in Smad2-deficient embryos [20].
  • We also identified Nodal as a Hex target in ES cells [21].
 

Analytical, diagnostic and therapeutic context of Hhex

References

  1. The homeobox gene Hex induces T-cell-derived lymphomas when overexpressed in hematopoietic precursor cells. George, A., Morse, H.C., Justice, M.J. Oncogene (2003) [Pubmed]
  2. Immunocytochemical characterization of murine Hex, a homeobox-containing protein. Ghosh, B., Ganea, G.R., Denson, L.A., Iannucci, R., Jacobs, H.C., Bogue, C.W. Pediatr. Res. (2000) [Pubmed]
  3. Apoptotic cell death in mouse models of GM2 gangliosidosis and observations on human Tay-Sachs and Sandhoff diseases. Huang, J.Q., Trasler, J.M., Igdoura, S., Michaud, J., Hanal, N., Gravel, R.A. Hum. Mol. Genet. (1997) [Pubmed]
  4. A direct gene transfer strategy via brain internal capsule reverses the biochemical defect in Tay-Sachs disease. Martino, S., Marconi, P., Tancini, B., Dolcetta, D., De Angelis, M.G., Montanucci, P., Bregola, G., Sandhoff, K., Bordignon, C., Emiliani, C., Manservigi, R., Orlacchio, A. Hum. Mol. Genet. (2005) [Pubmed]
  5. The organizer factors Chordin and Noggin are required for mouse forebrain development. Bachiller, D., Klingensmith, J., Kemp, C., Belo, J.A., Anderson, R.M., May, S.R., McMahon, J.A., McMahon, A.P., Harland, R.M., Rossant, J., De Robertis, E.M. Nature (2000) [Pubmed]
  6. Heart induction by Wnt antagonists depends on the homeodomain transcription factor Hex. Foley, A.C., Mercola, M. Genes Dev. (2005) [Pubmed]
  7. Impaired B cell development and function in mice with a targeted disruption of the homeobox gene Hex. Bogue, C.W., Zhang, P.X., McGrath, J., Jacobs, H.C., Fuleihan, R.L. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  8. A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels. Hallaq, H., Pinter, E., Enciso, J., McGrath, J., Zeiss, C., Brueckner, M., Madri, J., Jacobs, H.C., Wilson, C.M., Vasavada, H., Jiang, X., Bogue, C.W. Development (2004) [Pubmed]
  9. The homeobox gene HEX regulates proliferation and differentiation of hemangioblasts and endothelial cells during ES cell differentiation. Kubo, A., Chen, V., Kennedy, M., Zahradka, E., Daley, G.Q., Keller, G. Blood (2005) [Pubmed]
  10. Regulation of Hex gene expression by a Smads-dependent signaling pathway. Zhang, W., Yatskievych, T.A., Cao, X., Antin, P.B. J. Biol. Chem. (2002) [Pubmed]
  11. HNF3beta and GATA-4 transactivate the liver-enriched homeobox gene, Hex. Denson, L.A., McClure, M.H., Bogue, C.W., Karpen, S.J., Jacobs, H.C. Gene (2000) [Pubmed]
  12. Photoaffinity labeling of human lysosomal beta-hexosaminidase B. Identification of Glu-355 at the substrate binding site. Liessem, B., Glombitza, G.J., Knoll, F., Lehmann, J., Kellermann, J., Lottspeich, F., Sandhoff, K. J. Biol. Chem. (1995) [Pubmed]
  13. Pharmacological and kinetic properties of alpha 4 beta 2 neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes. Charnet, P., Labarca, C., Cohen, B.N., Davidson, N., Lester, H.A., Pilar, G. J. Physiol. (Lond.) (1992) [Pubmed]
  14. Characterization of the testis and epididymis in mouse models of human Tay Sachs and Sandhoff diseases and partial determination of accumulated gangliosides. Trasler, J., Saberi, F., Somani, I.H., Adamali, H.I., Huang, J.Q., Fortunato, S.R., Ritter, G., Gu, M., Aebersold, R., Gravel, R.A., Hermo, L. Endocrinology (1998) [Pubmed]
  15. Thyroid-specific transcription factors control Hex promoter activity. Puppin, C., D'Elia, A.V., Pellizzari, L., Russo, D., Arturi, F., Presta, I., Filetti, S., Bogue, C.W., Denson, L.A., Damante, G. Nucleic Acids Res. (2003) [Pubmed]
  16. Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas. Bort, R., Martinez-Barbera, J.P., Beddington, R.S., Zaret, K.S. Development (2004) [Pubmed]
  17. Hex: a homeobox gene revealing peri-implantation asymmetry in the mouse embryo and an early transient marker of endothelial cell precursors. Thomas, P.Q., Brown, A., Beddington, R.S. Development (1998) [Pubmed]
  18. Homeobox protein Hex induces SMemb/nonmuscle myosin heavy chain-B gene expression through the cAMP-responsive element. Sekiguchi, K., Kurabayashi, M., Oyama, Y., Aihara, Y., Tanaka, T., Sakamoto, H., Hoshino, Y., Kanda, T., Yokoyama, T., Shimomura, Y., Iijima, H., Ohyama, Y., Nagai, R. Circ. Res. (2001) [Pubmed]
  19. Retinoic acid generated by Raldh2 in mesoderm is required for mouse dorsal endodermal pancreas development. Molotkov, A., Molotkova, N., Duester, G. Dev. Dyn. (2005) [Pubmed]
  20. Postgastrulation Smad2-deficient embryos show defects in embryo turning and anterior morphogenesis. Heyer, J., Escalante-Alcalde, D., Lia, M., Boettinger, E., Edelmann, W., Stewart, C.L., Kucherlapati, R. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  21. Hex acts with {beta}-catenin to regulate anteroposterior patterning via a Groucho-related co-repressor and Nodal. Zamparini, A.L., Watts, T., Gardner, C.E., Tomlinson, S.R., Johnston, G.I., Brickman, J.M. Development (2006) [Pubmed]
  22. Hhex is a direct repressor of endothelial cell-specific molecule 1 (ESM-1). Cong, R., Jiang, X., Wilson, C.M., Hunter, M.P., Vasavada, H., Bogue, C.W. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  23. Expression of Hex mRNA in early murine postimplantation embryo development. Keng, V.W., Fujimori, K.E., Myint, Z., Tamamaki, N., Nojyo, Y., Noguchi, T. FEBS Lett. (1998) [Pubmed]
 
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