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      Expression of insulin-like 3 (INSL3) and differential splicing of its receptor in the ovary of rhesus macaques

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          Abstract

          Background

          Although insulin-like 3 (INSL3) has been identified in the gonad of both sexes in many species, there are only limited reports on the distribution of INSL3 and its receptor, relaxin/insulin-like family peptide receptor 2 (RXFP2), in the primate ovary. Since the hormone-receptor pair is believed to play a role in female reproduction, investigating the transcription of INSL3/RXFP2 genes and the spatiotemporal expression of INSL3 in the nonhuman primate may shed light on the functional aspects of the system in humans.

          Methods

          Database mining, molecular and immunological methods were applied.

          Results

          One single INSL3 transcript and three novel splice variant transcripts of RXFP2 were identified in the ovary of rhesus macaques. While the full-length RXFP2 transcript is barely detectable in granulosa cells during the periovulatory period, INSL3 transcript and protein are highly abundant in theca cells surrounding antral follicles. Moreover, the INSL3 level in follicular fluid is 3-4 times higher than that in female serum which remains low throughout the menstrual cycle.

          Conclusions

          The presence of INSL3 and its receptor in the ovary implies a potential role of the ligand-receptor pair in female reproduction in nonhuman primates. However, the existence of multiple splice variants of RXFP2 indicates a very complex nature of the hormone-receptor system.

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          Most cited references34

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          Zygote arrest 1 (Zar1) is a novel maternal-effect gene critical for the oocyte-to-embryo transition.

          The female gamete (the oocyte) serves the distinct purpose of transmitting the maternal genome and other maternal factors that are critical for post-ovulation events. Through the identification and characterization of oocyte-specific factors, we are beginning to appreciate the diverse functions of oocytes in ovarian folliculogenesis, fertilization and embryogenesis. To understand these processes further, we identified genes called zygote arrest 1 (Zar1 and ZAR1 in mouse and human, respectively) as novel oocyte-specific genes. These encode proteins of 361 amino acids and 424 amino acids, respectively, which share 59% amino-acid identity and an atypical plant homeo-domain (PHD) motif. Although Zar1-null (Zar1(-/-)) mice are viable and grossly normal, Zar1(-/-) females are infertile. Ovarian development and oogenesis through the early stages of fertilization are evidently unimpaired, but most embryos from Zar1(-/-) females arrest at the one-cell stage. Distinct pronuclei form and DNA replication initiates, but the maternal and paternal genomes remain separate in arrested zygotes. Fewer than 20% of the embryos derived from Zar1(-/-) females progress to the two-cell stage and show marked reduction in the synthesis of the transcription-requiring complex, and no embryos develop to the four-cell stage. Thus, Zar1 is the first identified oocyte-specific maternal-effect gene that functions at the oocyte-to-embryo transition and, as such, offers new insights into the initiation of embryonic development and fertility control in mammals.
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            Cryptorchidism in mice mutant for Insl3.

            L Parada, S Nef (1999)
            Impaired testicular descent (cryptorchidism) is one of the most frequent congenital abnormalities in humans, involving 2% of male births. Cryptorchidism can result in infertility and increases risk for development of germ-cell tumours. Testicular descent from abdomen to scrotum occurs in two distinct phases: the trans-abdominal phase and the inguino-scrotal phase. Currently, little is known about the factors that regulate the trans-abdominal phase of testicular descent. Leydig insulin-like hormone (Insl3) is a member of the insulin hormone superfamily expressed in the developing testis. We show here that mice mutant for Insl3 are viable, but exhibit bilateral cryptorchidism due to developmental abnormalities of the gubernaculum, resulting in abnormal spermatogenesis and infertility. Female homozygotes have impaired fertility associated with deregulation of the oestrus cycle. These findings reveal roles for Insl3 in the development of the urogenital tract and in female fertility. Insl3 may act as a hormone to regulate the growth and differentiation of the gubernaculum, thereby mediating intra-abdominal testicular descent.
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              Paracrine regulation of mammalian oocyte maturation and male germ cell survival.

              Mammalian oocytes are arrested at the prophase of meiosis before induction of maturation by the preovulatory luteinizing hormone (LH) surge. LH also promotes the survival of meiotic male germ cells in the testis. Because LH binds somatic cells, the mechanism underlying its regulation of germ cell function is unclear. We found that LH stimulates Leydig insulin-like 3 (INSL3) transcripts in ovarian theca and testicular Leydig cells. INSL3, in turn, binds a G protein-coupled receptor, LGR8 (leucine-rich repeat-containing G protein-coupled receptor 8), expressed in germ cells to activate the inhibitory G protein, thus leading to decreases in cAMP production. Treatment with INSL3 initiates meiotic progression of arrested oocytes in preovulatory follicles in vitro and in vivo and suppresses male germ cell apoptosis in vivo, thus demonstrating the importance of the INSL3-LGR8 paracrine system in mediating gonadotropin actions.
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                Author and article information

                Journal
                Reprod Biol Endocrinol
                Reproductive Biology and Endocrinology : RB&E
                BioMed Central
                1477-7827
                2010
                7 December 2010
                : 8
                : 150
                Affiliations
                [1 ]Division of Reproductive Sciences, Oregon National Primate Research Center, Oregon Health & Science University, West Campus, Beaverton, OR 97006, USA
                [2 ]Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR 97239, USA
                Article
                1477-7827-8-150
                10.1186/1477-7827-8-150
                3008693
                21138583
                e92aaae8-44d0-43e7-9bc4-cb43749c80bf
                Copyright ©2010 Hanna et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<url>http://creativecommons.org/licenses/by/2.0</url>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 September 2010
                : 7 December 2010
                Categories
                Research

                Human biology
                Human biology

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