Hyaluronan (HA) is an unbranched glycosaminoglycan composed of repeating disaccharide units. It is a major constituent of
the extracellular matrix and has been implicated in development, tumorigenesis, and several diseases. HA is synthesized at
the inner face of the plasma membrane and is subsequently extruded to the outside of the cell. senescence
NCBI Summary:
The protein encoded by this gene is involved in the synthesis of the unbranched glycosaminoglycan hyaluronan, or hyaluronic acid, which is a major constituent of the extracellular matrix. This gene is a member of the NODC/HAS gene family. Compared to the proteins encoded by other members of this gene family, this protein appears to be more of a regulator of hyaluronan synthesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2010]
General function
Enzyme
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Cellular localization
Plasma membrane
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Ovarian function
Preantral follicle growth, Cumulus expansion
Comment
Ovarian stiffness increases with age in the mammalian ovary and depends on collagen and hyaluronan matrices. Amargant F et al. (2020) Fibrosis is a hallmark of aging tissues which often leads to altered architecture and function. The ovary is the first organ to show overt signs of aging, including increased fibrosis in the ovarian stroma. How this fibrosis affects ovarian biomechanics and the underlying mechanisms are unknown. Using instrumental indentation, we demonstrated a quantitative increase in ovarian stiffness, as evidenced by an increase in Young's modulus, when comparing ovaries from reproductively young (6-12 weeks) and old (14-17 months) mice. This ovarian stiffness was dependent on collagen because ex vivo enzyme-mediated collagen depletion in ovaries from reproductively old mice restored their collagen content and biomechanical properties to those of young controls. In addition to collagen, we also investigated the role of hyaluronan (HA) in regulating ovarian stiffness. HA is an extracellular matrix glycosaminoglycan that maintains tissue homeostasis, and its loss can change the biomechanical properties of tissues. The total HA content in the ovarian stroma decreased with age, and this was associated with increased hyaluronidase (Hyal1) and decreased hyaluronan synthase (Has3) expression. These gene expression differences were not accompanied by changes in ovarian HA molecular mass distribution. Furthermore, ovaries from mice deficient in HAS3 were stiffer compared to age-matched WT mice. Our results demonstrate that the ovary becomes stiffer with age and that both collagen and HA matrices are contributing mechanisms regulating ovarian biomechanics. Importantly, the age-associated increase in collagen and decrease in HA are conserved in the human ovary and may impact follicle development and oocyte quality.//////////////////
Expression regulated by
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Ovarian localization
Oocyte, Granulosa, Theca
Comment
Naoko Kimura et al 2002 reported the expression of Hyaluronan Synthases and CD44
Messenger RNAs in Porcine Cumulus-Oocyte
Complexes During In Vitro Maturation.
The transient synthesis and accumulation of hyaluronan (HA), an extracellular matrix component of cumulus cells, brings
about expansion of cumulus-oocyte complexes (COCs) in preovulatory mammalian follicles. In this study, the authors investigated
the mRNA expressions of hyaluronan synthase 2 (has2), hyaluronan synthase 3 (has3), and CD44, as well as the
responsiveness to eCG and porcine follicular fluid (pFF) of these genes, in porcine COCs, oocytectomized complexes
(OXCs), and oocytes during in vitro maturation. Immunolocalization of CD44 was also analyzed in COCs. After 12 h of
culture, the area of cumulus expansion in medium 199 supplemented with both 10 IU/ml eCG and 10% (v/v) pFF was
significantly greater than that in the medium supplemented with eCG or pFF. Oocytectomy reduced the expansion area in the
group supplemented with eCG. In reverse transcription-polymerase chain reaction analysis, all transcripts were identified in
COCs, but has3 transcript was not found in OXCs. Only has3 mRNA was detectable in oocytes, indicating that cumulus cells
express has2 and CD44 mRNAs, and oocytes express has3 mRNA. The expression levels of has2 and CD44 mRNAs in
COCs and OXCs increased in the presence of eCG and pFF after 24 h of culture, suggesting that these genes have a positive
dependency on eCG and pFF. In contrast, the high level of has3 mRNA was detected in COCs cultured in the medium alone.
Oocytectomy slightly reduced the expression level of has2 mRNA. On immunostaining for CD44, CD44 was expressed
apparently in COCs cultured with eCG and pFF for 24 h. The positive staining was distributed on cytoplasm along the
perimembrane of cumulus cells and at the junctions between cumulus cells and oocytes. CD44 was also localized on
cytoplasm of some oocytes. These results indicate that 1) porcine oocytes promote eCG-dependent cumulus expansion and
the expression of has2 mRNA in cumulus cells, but these are not essential for expansion of cumulus cells and the expression
of has2 mRNA; 2) HAS2 is involved in HA synthesis during cumulus expansion, and eCG and pFF up-regulate its
expression; 3) the expression profile of the has3 mRNA that is transcribed in oocytes is different from those of has2 and
CD44 mRNA; and 4) CD44 may participate in the interaction between cumulus cells and oocytes.
Follicle stages
Antral, Preovulatory
Comment
Involvement of hyaluronan synthesis for ovarian follicle growth in rats. Takahashi N 2013 et al.
Most previous studies of ovarian HA have focused on mature antral follicles or corpora lutea, but scarcely on small preantral follicles. Moreover, the origin of follicular HA is unknown. To clarify the localization of HA and its synthases in small growing follicles, involvement of HA in follicle growth and gonadotropin regulation of HA synthase Has gene expression, perinatal, immature and adult ovaries of Wistar-Imamichi rats were examined histologically, biochemically and by in vitro follicle culture. HA was detected in the extracellular matrix of granulosa and theca cell layers of primary follicles and more advanced follicles. Ovarian HA accumulation ontogenetically started in the sex cords of perinatal animals, and its primary site shifted to the intrafollicular region of primary follicles within 5 days after birth. Messenger RNAs for Has1-3 were expressed in ovaries from perinatal, prepubertal and adult rats, and the expression levels of Has1 and Has2 genes were modulated during the estrous cycle in adults and following administration of exogenous gonadotropins in immature acyclic rats. Has1 and Has2 mRNAs were predominantly localized in the theca and granulosa cell layer of growing follicles, respectively. Treatments with chemicals that are known to reduce ovarian HA induced follicular atresia. More directly, addition of Streptomyces hyaluronidase, which specifically degrades HA, induced the arrest of follicle growth in an in vitro culture system. These results indicate that gonadotropin-regulated HA synthesis is involved in normal follicle growth.
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