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General Comment |
Hyaluronidases degrade hyaluronic acid (HA), a glycosaminoglycan present in the extracellular matrix of vertebrates.
By searching an EST database for sequences related to the PH-20 (OMIM: 600930) hyaluronidase, HYAL2 cDNA was identified. The HYAL2 cDNAs encode a preprotein with an N-terminal signal peptide.
NCBI Summary:
This gene encodes a weak acid-active hyaluronidase. The encoded protein is similar in structure to other more active hyaluronidases. Hyaluronidases degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. Hyaluronan and fragments of hyaluronan are thought to be involved in cell proliferation, migration and differentiation. Although it was previously thought to be a lysosomal hyaluronidase that is active at a pH below 4, the encoded protein is likely a GPI-anchored cell surface protein. This hyaluronidase serves as a receptor for the oncogenic virus Jaagsiekte sheep retrovirus. The gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression. This gene encodes two alternatively spliced transcript variants which differ only in the 5' UTR.[provided by RefSeq, Mar 2010]
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Comment |
Mammalian Hyaluronidase Induces Ovarian Granulosa Cell Apoptosis and Is Involved in Follicular Atresia. Orimoto AM et al. During ovarian folliculogenesis, the vast majority of follicles will undergo atresia by apoptosis, allowing a few dominant follicles to mature. Mammalian hyaluronidases comprise a family of 6-7 enzymes sharing the same catalytic domain responsible for hyaluronan hydrolysis. Interestingly, some of these enzymes have been shown to induce apoptosis. In the ovary, expression of three hyaluronidases (Hyal-1, Hyal-2 and Hyal-3) has been documented. However, their precise cellular localization and role in ovarian regulation have not yet been defined. We herein investigated the possible involvement of these enzymes in ovarian atresia. Firstly, we established a mouse model for ovarian atresia (gonadotropin withdrawal by anti-eCG treatment) and showed that the mRNA levels of Hyal-1, Hyal-2 and Hyal-3 were significantly increased in apoptotic granulosa cells as well as in atretic follicles. Secondly, using ovaries of normally cycling mice, we demonstrated the correlation of Hyal-1 mRNA and protein expression with cleavage of caspase-3. In addition, we showed that expression of all three hyaluronidases induced apoptosis in transfected granulosa cells. Significantly, the induction of apoptosis by hyaluronidases was independent of catalytic activity, since enzymatically inactive Hyal-1 mutant (D157A/E159A) was as efficient as the wild type enzyme in apoptosis induction. The activation of the extrinsic apoptotic signaling pathway was involved in this induction, as increased levels of cleaved caspase-8, caspase-3 and poly-ADP-ribose polymerase (PARP) were observed upon hyaluronidase ectopic expression. Our present findings provide a better understanding of the role of hyaluronidases in ovarian functions, showing for the first time their involvement in follicular atresia.
Critical role of Hyaluronidase-2 during preimplantation embryo development. Marei WF et al. Biological functions of hyaluronan (HA) depend on its molecular size. Small size HA are known to regulate cell proliferation, however the expression of HA synthases (HAS) and hyaluronidase (HYAL2) and their role during early embryo development have not been previously identified. In this paper we have shown by immunostaining that HA is produced by bovine in vitro-produced embryos at all stages of early development to blastocyst. Addition of HA-synthesis inhibitor (4MU) to in vitro embryo culture inhibited blastocyst formation. HA synthases HAS2 and HAS3 mRNA were expressed at all stages of embryo development; however, relative mRNA expression of HAS2 was significantly reduced as the embryos develop to blastocyst stage. HAS1 was detected during 2- and 4-cell stages but was barely detectable in subsequent stages. HYAL2 mRNA expression was detected in oviducts at early luteal phase but was only detected in the embryos at morula and blastocyst stages (day 6 and 7 post-fertilization). Addition of HYAL2 to embryo culture media at day 2 post-fertilization increased phosphorylated MAPK1 and 3 in the embryos and improved development to blastocyst stage and increased embryo cell numbers. Addition of Anti-CD44 antibody or MAPK inhibitor (U0126) abrogated the positive effects of HYAL2 on blastocyst rates. In conclusion, we demonstrate that expression of different HAS genes and HYAL2 in bovine embryos varies according to the stage of development, and that supplementation of HYAL2 in vitro mimics oviductal conditions and is shown to improve blastocyst rate and embryo quality, an effect which requires CD44 activity and MAPK signalling.
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