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Gene Review

Has2  -  hyaluronan synthase 2

Mus musculus

Synonyms: HA synthase 2, Hyaluronan synthase 2, Hyaluronate synthase 2, Hyaluronic acid synthase 2
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Disease relevance of Has2

  • Sequence comparisons indicated that mouse Has3 is most closely related to Has2 (71% amino acid identity) and also related to Has1 (57% identity), Xenopus laevis DG42 (56% identity), and Streptococcus pyogenes HasA (28% identity) [1].

High impact information on Has2

  • Collectively, our results demonstrate the importance of HA in mammalian embryogenesis and the pivotal role of Has2 during mammalian development [2].
  • Heart explants from Has2(-/-) embryos lack the characteristic transformation of cardiac endothelial cells into mesenchyme, an essential developmental event that depends on receptor-mediated intracellular signaling [2].
  • Natural antisense mRNAs to hyaluronan synthase 2 inhibit hyaluronan biosynthesis and cell proliferation [3].
  • Furthermore, the Has2 and Has3 genes are identical in structure, suggesting that they arose by a gene duplication event early in vertebrate evolution [4].
  • Transfection experiments demonstrated that mouse Has2 could direct hyaluronan coat biosynthesis in transfected COS cells, as evidenced by a classical particle exclusion assay [5].

Biological context of Has2

  • The current study defines the embryonic expression pattern of Has2 and explores the regulation of Has2 gene expression by Bmp signaling [6].
  • Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme [2].
  • Results showed that the equine HAS2 cDNA contains a 5'-untranslated region of 436 bp, an open reading frame of 1659 bp, and a 3'-untranslated region of 707 bp [7].
  • The regulation of HAS2 mRNA was studied in equine follicles isolated during estrus between 0 and 39 h after an ovulatory dose of hCG and in corpora lutea obtained on d 8 of the estrous cycle [7].
  • The objectives of this study were to clone and characterize equine hyaluronan synthase 2 (HAS2) and investigate the regulation of its transcript and of HA synthesis in equine follicles during human chorionic gonadotropin (hCG)- induced ovulation [7].

Anatomical context of Has2

  • In dermis, the number of cells expressing the Has1 mRNA was less than that of the Has2 mRNA, and in epidermis, some strong signals from both mRNA were seen in stratum granulosum [8].
  • After E8.5, Has1 expression disappears, but Has2 continues to be strongly, albeit transiently, expressed in numerous tissues, including the branchial arches and craniofacial structures such as the palatal shelves and lens pit [9].
  • Notably, Has3 expression in the developing teeth, vibrissae hair follicles, nasal cavity, and inner ear complements the expression pattern of Has2 [9].
  • Supporting this observation, Has2 and Ptgs2 mRNA levels after 8 h of coculture were lower in cumulus cells cocultured with Gdf9 dsRNA-injected oocytes than in those cocultured with buffer-injected oocytes [10].
  • We previously showed reduction in Has2 expression and diminished presence of HA at later stages of heart development as tissue remodeling formed the leaflets of the cardiac valves [11].

Associations of Has2 with chemical compounds

  • We have developed a crosslinked hyaluronic acid (HA) film with DNA incorporated within its structure and have characterized this system for its efficacy in sustained transferring of a vector encoding mouse hyaluronan synthase 2 (Has2) [12].
  • HAS2 expression is suppressed in mice treated with progesterone [13].
  • The steroid 5alpha-reductase type 1 deficient mouse, which fails to undergo cervical remodeling, has decreased expression of HAS2 mRNA and decreased tissue HA [13].

Regulatory relationships of Has2

  • Monoclonal neutralizing antibody-GDF9-53 attenuated GDF9-induced OOX HAS2 expression but not oocyte-induced HAS2 expression [14].

Analytical, diagnostic and therapeutic context of Has2

  • To investigate the role of GDF9 in cumulus expansion, two endpoints were used to evaluate cumulus expansion: Has2 and Ptgs2 mRNA levels were measured in cumulus cells using real-time RT-PCR, and assessment of cumulus expansion was undertaken morphologically [10].
  • More specifically, in this review we will provide an overview of the conditional gene targeting strategy being used to create tissue-specific deficiencies in Has2 function, along with our progress in understanding the role for Has3-dependent HA biosynthesis [15].
  • In situ hybridization studies demonstrate dynamic Has2 expression patterns during myocardial cell development and cardiac tube formation, formation of the cardiac endocardial cushions, and cushion invasion by valve primordial cells [6].
  • Results from semiquantitative RT-PCR/Southern blotting analyses revealed a transient induction of HAS2 during the ovulatory process [7].


  1. Molecular cloning and characterization of a cDNA encoding the third putative mammalian hyaluronan synthase. Spicer, A.P., Olson, J.S., McDonald, J.A. J. Biol. Chem. (1997) [Pubmed]
  2. Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. Camenisch, T.D., Spicer, A.P., Brehm-Gibson, T., Biesterfeldt, J., Augustine, M.L., Calabro, A., Kubalak, S., Klewer, S.E., McDonald, J.A. J. Clin. Invest. (2000) [Pubmed]
  3. Natural antisense mRNAs to hyaluronan synthase 2 inhibit hyaluronan biosynthesis and cell proliferation. Chao, H., Spicer, A.P. J. Biol. Chem. (2005) [Pubmed]
  4. Characterization and molecular evolution of a vertebrate hyaluronan synthase gene family. Spicer, A.P., McDonald, J.A. J. Biol. Chem. (1998) [Pubmed]
  5. Molecular cloning and characterization of a putative mouse hyaluronan synthase. Spicer, A.P., Augustine, M.L., McDonald, J.A. J. Biol. Chem. (1996) [Pubmed]
  6. Has2 expression in heart forming regions is independent of BMP signaling. Klewer, S.E., Yatskievych, T., Pogreba, K., Stevens, M.V., Antin, P.B., Camenisch, T.D. Gene Expr. Patterns (2006) [Pubmed]
  7. Induction of hyaluronan synthase 2 by human chorionic gonadotropin in mural granulosa cells of equine preovulatory follicles. Stock, A.E., Bouchard, N., Brown, K., Spicer, A.P., Underhill, C.B., Doré, M., Sirois, J. Endocrinology (2002) [Pubmed]
  8. Putative hyaluronan synthase mRNA are expressed in mouse skin and TGF-beta upregulates their expression in cultured human skin cells. Sugiyama, Y., Shimada, A., Sayo, T., Sakai, S., Inoue, S. J. Invest. Dermatol. (1998) [Pubmed]
  9. Three vertebrate hyaluronan synthases are expressed during mouse development in distinct spatial and temporal patterns. Tien, J.Y., Spicer, A.P. Dev. Dyn. (2005) [Pubmed]
  10. RNA interference evidence that growth differentiation factor-9 mediates oocyte regulation of cumulus expansion in mice. Gui, L.M., Joyce, I.M. Biol. Reprod. (2005) [Pubmed]
  11. Depolymerized hyaluronan induces vascular endothelial growth factor, a negative regulator of developmental epithelial-to-mesenchymal transformation. Rodgers, L.S., Lalani, S., Hardy, K.M., Xiang, X., Broka, D., Antin, P.B., Camenisch, T.D. Circ. Res. (2006) [Pubmed]
  12. Delivery of a vector encoding mouse hyaluronan synthase 2 via a crosslinked hyaluronan film. Kim, A.P., Yellen, P., Yun, Y.H., Azeloglu, E., Chen, W. Biomaterials (2005) [Pubmed]
  13. Regulation of hyaluronan expression during cervical ripening. Straach, K.J., Shelton, J.M., Richardson, J.A., Hascall, V.C., Mahendroo, M.S. Glycobiology (2005) [Pubmed]
  14. Role of oocyte-secreted growth differentiation factor 9 in the regulation of mouse cumulus expansion. Dragovic, R.A., Ritter, L.J., Schulz, S.J., Amato, F., Armstrong, D.T., Gilchrist, R.B. Endocrinology (2005) [Pubmed]
  15. Investigation of hyaluronan function in the mouse through targeted mutagenesis. Spicer, A.P., Tien, J.L., Joo, A., Bowling Jr, R.A. Glycoconj. J. (2002) [Pubmed]
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