| insulin like 3 | OKDB#: 57 |
| Symbols: | INSL3 | Species: | human | ||
| Synonyms: | RLF, RLNL, ley-I-L | Locus: | 19p13.11 in Homo sapiens |
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| General Comment |
New theca-cell marker insulin-like factor 3 is associated with premature ovarian insufficiency. Zhu C et al. (2020) To characterize circulating insulin-like factor 3 (INSL3) in different stages of ovarian insufficiency and its role in the evaluation of premature ovarian insufficiency (POI). Retrospective cohort study. University-based center for reproductive medicine. A total of 145 women, including 48 patients with POI (25 IU/L < follicle-stimulating hormone FSH] ≤40 IU/L), 49 with biochemical POI (bPOI) (10 IU/L < FSH ≤25 IU/L) and 48 age-matched control women with normal ovarian reserve (FSH <10 IU/L), retrospectively included from the reproductive hospital affiliated with Shandong University between 2017 and 2019. Levels of INSL3 in the serum and follicular fluid assayed with a commercial radioimmunoassay. Level of INSL3 in serum and follicular fluid among control women and patients with bPOI and POI, its association with different ovarian reserve markers, and its predictive value for bPOI and POI. The serum INSL3 level continuously declined with the progress of ovarian insufficiency. It showed strong negative association with FSH (-0.655) and luteinizing hormone (-0.433), but positively correlated with antimüllerian hormone (0.617), inhibin B (0.400), antral follicle count (0.630), and testosterone (0.180). Additionally, the circulating INSL3 served as a good predictor for bPOI and POI. No statistically significant difference of INSL3 levels in follicular fluid was observed between bPOI patients and control women. For the first time our study has revealed an INSL3 deficiency in women with POI, indicating that circulating INSL3 could serve as a promising theca-cell specific marker for POI. Future research on the role of INSL3 in modulating follicular development, steroidogenesis, and POI pathogenesis is warranted.//////////////////
Evolution of a splice variant that acts as an endogenous antagonist of the original INSL3 in primates. [Yang N et al. (2020) Alu sequences are the most abundant repetitive elements in the human genome, and have proliferated to more than one million copies in the human genome. Primate-specific Alu sequences account for ∼10% of the human genome, and their spread within the genome has the potential to generate new exons. The new exons produced by Alu elements appear in various primate genes, and their functions have been elucidated. Here, we identified a new exon in the insulin-like 3 gene (INSL3), which evolved ∼50 million years ago, and led to a splicing variant with 31 extra amino acid residues in addition to the original 95 nucleotides (NTs) of INSL3. The Alu-INSL3 isoform underwent diverse changes during primate evolution; we identified that human Alu-INSL3 might be on its way to functionality and has potential to antagonize LGR8-INSL3 function. Therefore, the present study is designed to provide an example of the evolutionary trajectory of a variant peptide hormone antagonist that caused by the insertion of an Alu element in primates.//////////////////
Relaxin-like factor (RLF) is a member of the insulin/insulin-like growth factor family of hormones and growth factors, which appears to be predominantly expressed in the Leydig cells of the testis.
Kumagai J, et al 2002 reported that INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent.The active form of goat insulin-like peptide 3 (INSL3) is a single-chain structure comprising three domains B-C-A, constitutively expressed and secreted by testicular Leydig cells. Qin S 2013 et al.
Abstract Relaxin-like factor (RLF), also called insulin-like peptide 3 (INSL3), is a member of the insulin/relaxin gene family and is produced by testicular Leydig cells. While the understanding of its effects is growing, very little is known about the structural and functional properties of native INSL3. Here, we demonstrate that native INSL3 isolated from goat testes is a single-chain structure with full biological activity, and is constitutively expressed and secreted by Leydig cells. Using a series of chromatography steps, native INSL3 was highly purified as a single 12-kDa peak as revealed by SDS-PAGE. MS/MS analysis provided 81% sequence coverage and revealed a distinct single-chain structure consisting of the B-, C-, and A-domains deduced previously from the INSL3 cDNA sequence. Moreover, the N-terminal peptide was six amino acid residues longer than predicted. Native INSL3 exhibited full bioactivity in HEK-293 cells expressing the receptor for INSL3. Immunoelectron microscopy and Western blot analysis revealed that INSL3 was secreted by Leydig cells through the constitutive pathway into blood and body fluids. We conclude, therefore, that goat INSL3 is constitutively secreted from Leydig cells as a B-C-A single-chain structure with full biological activity.
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Several orphan G protein-coupled receptors homologous to gonadotropin and thyrotropin receptors have recently been identified and named as LGR4-8. INSL3, also known as Leydig insulin-like peptide or relaxin-like factor, is a relaxin family member expressed in testis Leydig cells and ovarian theca and luteal cells. Male mice mutant for INSL3 exhibit cryptorchidism or defects in testis descent due to abnormal gubernaculum development whereas overexpression of INSL3 induces ovary descent in transgenic females. Because transgenic mice missing the LGR8 gene are also cryptorchid, INSL3 was tested as the ligand for LGR8. The authors show that treatment with INSL3 stimulated cAMP production in cells expressing recombinant LGR8, but not LGR7. In addition, interactions between INSL3 and LGR8 were demonstrated following ligand receptor cross-linking. Northern blot analysis indicated that the LGR8 transcripts are expressed in gubernaculum whereas treatment of cultured gubernacular cells with INSL3 stimulated cAMP production and thymidine incorporation. The present study identified the ligand for an orphan GPCR based on common phenotypes of ligand and receptor null mice. Demonstration of INSL3 as the ligand for LGR8 facilitates understanding of the mechanism of testis descent and allows studies on the role of INSL3 in gonadal and other physiological processes.///////thecal cell marker
NCBI Summary: This gene encodes a member of the insulin-like hormone superfamily. The encoded protein is mainly produced in gonadal tissues. Studies of the mouse counterpart suggest that this gene may be involved in the development of urogenital tract and female fertility. This protein may also act as a hormone to regulate growth and differentiation of gubernaculum, and thus mediating intra-abdominal testicular descent. Mutations in this gene may lead to cryptorchidism. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2012] |
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| General function | Ligand, Hormone, Growth factor | ||||
| Comment | Parallel variations of insulin-like peptide 3 (INSL3) and Anti-mullerian hormone (AMH) in women with the polycystic ovary syndrome according to menstrual cycle pattern. Pelusi C 2013 et al. Context:Anti-m?an hormone (AMH) and insulin-like factor 3 (INSL3) represent ovarian functional markers of granulosa and theca cells respectively.Objective:We conducted a prospective study to investigate AMH and INSL3 plasma levels in three groups of polycystic ovary syndrome (PCOS) women classified according to menstrual cyclicity pattern and their relationship with ovarian morphology and hormonal levels.Design and Participants.AMH and INSL3 were measured in a cohort of 57 patients with PCOS, divided into three groups according to menstrual status: eumenorrhea (PCOS-E, n: 15), oligomenorrhea (PCOS-O, n: 25) and amenorrhea (PCOS-A, n:17). Clinical and endocrine characteristics and ovarian morphology were compared between the groups. Twenty-seven age- and weight- matched women without hyperandrogenism were included as controls.Results.According to menstrual pattern, the PCOS-A and PCOS-O women had higher INSL3 levels with respect to controls (P=0.025 and P=0.004, respectively) and higher but not significant INSL3 levels compared to PCOS-E women. AMH levels were significantly higher in PCOS-A and PCOS-O women with respect to PCOS-E women (P<0.001 and P< 0.001, respectively) and controls (P<0.001 and P<0.001, respectively). Interestingly, a significant positive correlation was found between INSL3 and AMH blood levels in all PCOS women (R=0,43; P=0,002) and across the groups (R=0.41; P<0.001).Conclusion:INSL3 and AMH levels are significantly correlated with each other in PCOS women and they are significantly increased particularly in the presence of amenorrhea and oligomenorrhea. INSL3 and AMH may reflect a dysfunction of PCOS thecal and granulosa cells which are responsible for increased androgen production and chronic anovulation of this condition. ///////////////////////// | ||||
| Cellular localization | Secreted | ||||
| Comment | candidate123 ///// Anti-müllerian hormone and insulin-like 3 levels in healthy normal-weight ovulatory and anovulatory eumenorrheic late adolescent females: potential early biomarkers of ovarian dysfunction? Pelusi C et al. (2015) The aim of this study was to evaluate differences in anti-müllerian hormone (AMH) and insulin-like 3 (INSL3) levels and their association with gonadotropin and ovarian steroid hormones, as expression of ovarian function, between healthy normal-weight ovulatory and anovulatory eumenorrheic late adolescent females. This study analyzed AMH and INSL3 levels in forty healthy eumenorrheic late adolescent females (aged 16-19 ys), selected from a cross-sectional epidemiological study performed on the prevalence of hyperandrogenic states. The subjects were divided into ovulatory (n: 28) and anovulatory (n: 12) groups in accordance to a previous cluster analysis based on progesterone (P) distribution measured once in the latter part of the cycle. Both groups were compared for anthropometric, biochemical and hormonal parameters. INSL3 and AMH were detectable in all samples. Testosterone (P=0.01), the free-androgen index (FAI) (P=0.051), gonadotropins (LH: P=0.02; FSH: P=0.004) and AMH (P=0.02) levels were significantly higher in the anovulatory group with respect to their ovulatory counterpart. A trend toward significantly higher INSL3 concentrations (P=0.08) was also shown in the anovulatory group. A positive correlation between INSL3 levels and androgens such as androstenedione (r=0.38; P=0.02), testosterone (r=0.44; P=0.004) and FAI (r=0.42; P=0.006) and a negative borderline significant correlation (r=-0.30; P=0.055) between AMH and P were shown in all subjects. Healthy eumenorrheic late adolescent females with sporadic anovulation display higher AMH and INSL-3 blood concentrations in association with higher androgen levels compared with age- and BMI-matched subjects with ovulatory cycle, suggesting evidence of an earlier ovarian dysfunction.////////////////// GREAT/LGR8 is the Only Receptor for Insulin-Like 3 Peptide Bogatcheva NV, et al During male development testes descend from their embryonic intraabdominal position into the scrotum. Two genes, encoding the INSL3 hormone and the GREAT/LGR8 G protein-coupled receptor, control the differentiation of gubernaculum, the caudal genitoinguinal ligament, critical for the testicular descent. It was established that the INSL3 peptide activates GREAT/LGR8 receptor in vitro. Mutations of Insl3 or Great cause cryptorchidism (undescended testes) in mice. Overexpression of the transgenic Insl3 causes male-like gubernaculum differentiation, ovarian descent into lower abdominal position, and reduced fertility in females. To address the question whether Great deletion complements the mutant female phenotype caused by the Insl3 overexpression, we have produced Insl3 transgenic mice deficient for Great. Such females had a wild-type phenotype, demonstrating that Great was the only cognate receptor for Insl3 in vivo. We have established that HIT cells, transfected with the INSL3 cDNA, produce functionally active hormone. Analysis of five INSL3 mutant variants detected in the cryptorchid patients showed that P49S substitution renders functionally compromised peptide. Therefore, mutations in INSL3 might contribute to the etiology of cryptorchidism. We have also showed that synthetic insulin-like peptides (INSL4 and INSL6) were unable to activate LGR7 or GREAT/LGR8. | ||||
| Ovarian function |
Preantral follicle growth, Follicle atresia, Luteolysis, Oocyte maturation
, Germinal vesicle breakdown |
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| Comment | Kawamura K, et al reported 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.///// Theca Cell INSL3 and Steroids Together Orchestrate the Growing Bovine Antral Follicle. Dai Y et al. (2018) Insulin-like peptide 3 (INSL3) and its specific receptor RXFP2 are both expressed by theca interna cells of the growing antral follicle where they form an essential regulatory element in the production of the steroid precursor androstenedione. Using primary cultures of bovine theca cells from the mid follicular phase together with steroid agonists and antagonists we have examined how ovarian steroids modulate INSL3 expression. Transcript analysis shows that these cells express estrogen receptors α and β, androgen and progesterone receptors, besides the orphan nuclear receptors SF1 and nur77. Whereas, exogenous androgens have little or no effect, the androgen antagonist bicalutamide stimulates INSL3 production. In contrast, estrogen receptor agonists, as also progesterone, are stimulatory. Importantly, estrogen receptor signaling is convergent with the protein kinase A signaling pathway activated by LH, such that the estrogen receptor antagonist can inhibit the mild stimulatory effect of LH, and vice versa the PKA antagonist H89 blocks stimulation by estradiol. A significant finding is that the major steroid metabolite androstenedione appears to act predominantly as an estrogen and not an androgen in this system. Transfection of INSL3 gene promoter-reporter constructs together with various steroid receptor expression plasmids supports these findings and shows that steroid action uses non-classical pathways not requiring canonical steroid-responsive elements in the proximal promoter region. Together, the results indicate that increasing estrogens in the follicular phase stimulate a feedforward loop driving INSL3 signaling and thereby promoting steroidogenesis in the growing antral follicle until the LH surge which effectively switches off INSL3 expression.////////////////// ///////////////////////// Insulin-like 3 induced rat preantral follicular growth is mediated by growth differentiation factor 9. Xue K 2013 et al. The communication of somatic cells and oocyte by intrafollicular paracrine factors is essential for follicular growth in the ovary. Insulin-like 3 (INSL3) is a theca cell-secreted paracrine factor. Androgens and growth differentiation factor 9 (GDF9), an oocyte-derived growth factor, are essential for follicular development. Using a rat preantral follicle culture model, we examined in the present study the influence of INSL3 on preantral follicular growth and the molecular mechanisms involved. We have observed that the receptor for INSL3, relaxin/insulin-like family peptide receptor 2 (RXFP2), was exclusively expressed in oocyte. Recombinant INSL3 stimulated Gdf9 expression, preantral follicular growth and testosterone synthesis in vitro. Inhibition of the cAMP/PKA signaling pathway (with cAMP anatagonist, Rp-8-Br-cAMPS) attenuated INSL3-induced Gdf9 expression and preantral follicular growth. Moreover, knocking down Gdf9 expression (siRNA) or inhibiting GDF9 signaling with SB431542 (ALK5 inhibitor) or SIS3 (SMAD3 inhibitor), or androgen action with flutamide /androgen receptor antagonist/ suppressed INSL3-induced preantral follicular growth. In addition, LH and DHT regulated the expression of Insl3 mRNA in preantral follicles. These observations suggest that INSL3 is a key theca cell-derived growth factor for preantral follicle and that its action is mediated by GDF9. ///////////////////////// /////// INSULIN-LIKE FACTOR 3: A NEW CIRCULATING HORMONE RELATED TO LH-DEPENDENT OVARIAN HYPERANDROGENISM IN THE POLYCYSTIC OVARY SYNDROME. [Gambineri A et al. Insulin-like factor 3 (INSL3), a member of the relaxin-insulin family, is produced in the Leydig cells and at reduced levels in ovarian theca interna cells of antra follicles as well as in the corpora lutea and ovarian stroma. Among the factors potentially involved in the stimulation of gonadal expression of INSL3, recent data obtained in rats show an important role of LH. Ovaries from most women affected by polycystic ovary syndrome (PCOS) are characterized by hyperplasia of the theca interna and of cortical stroma and by an increased number of small antral follicles, and the majority of women with PCOS, particularly normal-weight subjects, have LH levels that are above the normal range. To investigate INSL3 circulating levels in both normal-weight and overweight-obese PCOS women, and the association of INSL3 with gonadotropin and androgenic pattern and with ovarian morphology. Design: Controlled study. Setting: Academic Hospital. Participants: 44 PCOS patients (22 normal-weight and 22 overweight-obese) and 44 controls comparable for age and body weight. Main outcome measures: INSL3 serum concentrations, measured by radioimmunoassay, in PCOS patients and controls, and their correlation with clinical and biochemical phenotype and with ovarian morphology. INSL3 serum concentrations were significantly higher in PCOS patients with respect to controls (P=0.003), particularly in normal-weight (P=0.001), but not in overweight-obese (P=0.312) PCOS patients. INSL3 serum concentrations were positively correlated with total- and free-testosterone and with LH levels in all women (total testosterone, P<0.001; free testosterone, P=0.001; LH, P=0.002) as well as in PCOS patients (total testosterone, P=0.024; free testosterone, P=0.045; LH, P=0.049). Moreover, in the PCOS group, INSL3 levels were related to a greater 17OH-progesterone response to buserelin (P=0.015), an index of ovarian hyperandrogenism. Finally, in PCOS women, INSL3 levels were positively correlated with ovarian follicle number (P= 0.028). Conclusions: INSL3 could be considered a new circulating hormone related to LH-dependent ovarian hyperandrogenism, particularly in normal-weight PCOS women. =Basal Insulin-Like Factor 3 Levels Predict Functional Ovarian Hyperandrogenism in the Polycystic Ovary Syndrome. Gambineri A et al. Aim. The aims of the study were to understand the association between Insulin-Like Factor 3 (INSL3) and functional ovarian hyperandrogenism (FOH) in PCOS and the regulatory role played by LH. Subjects and Methods. Fifteen PCOS women were classified as FOH (FOH-PCOS, n= 8) and non-FOH (NFOHPCOS, n= 7) according to the response of 17OH-progesterone to buserelin (a GnRH analogue) with respect to 15 controls. FOH-PCOS and NFOH-PCOS were compared for basal INSL3 levels. In addition, the effect of buserelin on INSL3 concentrations and the relationship between basal and buserelin-stimulated LH and 17OH-progesterone and INSL3 were evaluated. Results. Basal INSL3 levels were higher in FOH-PCOS than NFOH-PCOS (P= 0.001) and controls (P=0.001), whereas they did not differ between NFOH-PCOS and controls. In addition, FOH-PCOS had a higher response of LH to buserelin with respect to NFOH-PCOS. Within all PCOS women the levels of INSL3 positively correlated with FT (P= 0.022) and negatively with SHBG (r= P=0.031). Moreover, positive correlations with the absolute increase of 17OH-progesterone (P< 0.001) and with the LHAUC (P=0.001) after buserelin administration were found. In the multiple regression analysis INSL3 persisted significantly correlated only with 17OH-progesterone response to buserelin. Finally, INSL3 was not significantly modified after buserelin administration either in FOH-PCOS or in NFOH-PCOS. Conclusions. These data suggest that INSL3 is related to FOH in PCOS women, but this association seems not to be mediated by LH, further reinforcing the concept that a pathophysiological heterogeneity for ovarian hyperandrogenism in PCOS exists. | ||||
| Expression regulated by | LH, Steroids, Growth Factors/ cytokines, bmp6 | ||||
| Comment | Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production. Glister C et al. Bone morphogenetic proteins (BMPs) are firmly implicated as intra-ovarian regulators of follicle development and steroidogenesis. Here we report a microarray analysis showing that treatment of cultured bovine theca cells (TC) with BMP6 significantly (>twofold; P < 0.01) up- or down-regulated expression of 445 genes. Insulin-like peptide 3 (INSL3) was the most heavily down-regulated gene (-43-fold) with cytochrome P450, subfamily XVII (CYP17A1) and other key steroidogenic transcripts including steroidogenic acute regulatory protein (STAR), cytochrome P450 family 11, subfamily A1 (CYP11A1) and 3 beta-hydroxysteroid dehydrogenase type 1 (HSD3B1) also down-regulated. BMP6 also reduced expression of nuclear receptor subfamily 5A1 (NR5A1) known to target the promoter regions of the aforementioned genes. Real-time PCR confirmed these findings and also revealed a marked reduction in expression of INSL3 receptor, relaxin/insulin-like family peptide receptor 2 (RXFP2). Secretion of INSL3 protein and androstenedione were also suppressed suggesting a functional link between BMP and INSL3 pathways in controlling androgen synthesis. RNAi-mediated knockdown of INSL3 reduced INSL3 mRNA (75%) and protein (94%) level and elicited a 77% reduction in CYP17A1 mRNA and 83% reduction in androstenedione secretion. Knockdown of RXFP2 also reduced CYP17A1 expression (81%) and androstenedione secretion (88%). Conversely, treatment with exogenous (human) INSL3 increased androstenedione secretion ~twofold. The CYP17A1 inhibitor abiraterone abolished androgen secretion and reduced expression of both INSL3 and RXFP2. Collectively, these findings indicate a positive autoregulatory role for INSL3 signaling in maintaining thecal androgen production, and visa versa. Moreover, BMP6-induced suppression of thecal androgen synthesis may be mediated, at least in part, by reduced INSL3-RXFP2 signaling. | ||||
| Ovarian localization | Granulosa, Theca, Luteal cells | ||||
| Comment | Ovarian Expression of Insulin-Like Peptide 3 (INSL3) and Its Receptor (RXFP2) During Development of Bovine Antral Follicles and Corpora Lutea and Measurement of Circulating INSL3 Levels During Synchronized Estrous Cycles. Satchell L et al. Insulin-like peptide 3 (INSL3), a major product of testicular Leydig cells, is also expressed by the ovary, but its functional role remains poorly understood. Here, we quantified expression of INSL3 and its receptor RXFP2 in theca interna cell (TIC) and granulosa cell compartments of developing bovine antral follicles and in corpora lutea (CL). INSL3 and RXFP2 mRNA levels were much higher in TIC than granulosa cell and increased progressively during follicle maturation with INSL3 peaking in large (11-18 mm) estrogen-active follicles and RXFP2 peaking in 9- to 10-mm follicles before declining in larger (11-18 mm) follicles. Expression of both INSL3 and RXFP2 in CL was much lower than in TIC. In situ hybridization and immunohistochemistry confirmed abundant expression of INSL3 mRNA and protein in TIC. These observations indicate follicular TIC rather than CL as the primary site of both INSL3 production and action, implying a predominantly autocrine/paracrine role in TIC. To corroborate the above findings, we showed that in vitro exposure of TIC to a luteinizing concentration of LH greatly attenuated expression of both INSL3 and its receptor while increasing progesterone secretion and expression of STAR and CYP11A1. Moreover, in vivo, a significant cyclic variation in plasma INSL3 was observed during synchronized estrous cycles. INSL3 and estradiol-17?followed a similar pattern, both increasing after luteolysis, before falling sharply after the LH surge. Thus, theca-derived INSL3, likely from the dominant preovulatory follicle, is detectable in peripheral blood of cattle, and expression is down-regulated during luteinization induced by the preovulatory LH surge. Collectively, these findings underscore the likely role of INSL3 as an important intrafollicular modulator of TIC function/steroidogenesis, while raising doubts about its potential contribution to CL function. Bamberger et al. (1999) found that RLF is expressed in hilus (Leydig) cells and theca interna cells but absent in granulosa cells, ovarian stromal cells, and surface epithelium. RLF expression was also observed in the corpus luteum, although at a lower level than in theca cells.Klonisch T, et al 2001 reported the expression of immunoreactive RLF and relaxin. Within the ovary, RLF, but not relaxin, was detected in follicular theca interna and granulosa cells and the corpus luteum. Spiess AN, et al 1999 Structure and expression of the rat relaxin-like factor (RLF) gene. The relaxin-like factor (RLF) is a novel member of the insulin-IGF-relaxin family of growth factors and hormones, and its mRNA is expressed very specifically in the Leydig cells of the testis and in the theca and luteal cells of the ovary. The authors reported the cloning of the RLF gene and cDNA from the rat. The 0.8kb mRNA is produced from a small gene comprising two exons situated less than 1 kb downstream of the gene for the signalling factor JAK3. Northern hybridization confirms high RLF mRNA expression in the adult rat testis, and low expression in the ovary, but in no other tissues examined. Northern analysis of fetal and neonatal gonadal tissues showed that RLF mRNA is highly upregulated in the testes of day 19 embryos, but not in later neonatal stages, nor in any ovarian tissue from this period. Immunohistochemical localization of relaxin-like factor/insulin-like Peptide-3 in the bovine corpus luteumNichols N, et al . Relaxin-like factor/insulin-like peptide (INSL)-3 is highly expressed in the bovine corpus luteum throughout the estrous cycle and pregnancy. Demonstration of translation of the relaxin-like factor message was previously shown for the follicle but not the corpus luteum. In this study, relaxin-like factor mRNA was highly expressed in the corpus luteum on days 7 and 14 of pregnancy. Tissues were fixed in 10% neutral buffered formalin, and utilizing two different antibodies to relaxin-like factor, W3 rabbit anti-bovine and 2-8F mouse anti-bovine, relaxin-like factor was localized in fibroblast-like cells. Staining was also observed in the Leydig cells of bovine testicular tissue. No staining was observed in small and large steroidogenic luteal cells, indicating a nonsteroidogenic source of luteal relaxin-like factor. Definitive cell type identification is currently being determined via electron microscopy. Expression of insulin-like 3 (INSL3) and differential splicing of its receptor in the ovary of rhesus macaques. Hanna CB et al. 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. | ||||
| Follicle stages | Antral, Preovulatory, Corpus luteum | ||||
| Comment | Tashima LS, et al reported that the human Leydig insulin-like (hLEY I-L) gene is expressed in the corpus luteum and trophoblast. They detected hLey I-L gene expression in the cyclic human corpus luteum and trophoblast by the reverse transcriptase-polymerase chain reaction (RT-PCR), with primers selected from the published human Ley I-L sequence. In Northern analyses; hybridization was readily shown with cyclic corpora lutea but not with other tissues. Hombach-Klonisch S, et al have cloned the coding cDNA sequence for the RLF, also known as Insl3, of the fallow deer. The RLF coding sequence consisted of 396 bp encoding a peptide of 131 amino acids and shared highest homology with bovine, sheep and goat RLF. Northern analysis revealed a single 0.9 kb transcript in the deer testis. There is only one RLF gene in the deer genome. Nonradioactive in situ hybridization revealed the Leydig cells to be the sole source for RLF mRNA in the deer testis. In the non-pregnant uterus, RLF transcripts were located in the luminal and glandular epithelium of the endometrium. Within the ovary of the pregnant doe, follicular theca interna cells and the corpus luteum expressed RLF transcripts. In uteroplacental tissues, luminal and glandular epithelium, fetal uninucleate and binucleate trophoblast cells (BNC) of the basic villous trophoblast layer expressed RLF mRNA. BNC located at the apical trophoblast layer or the tip of the fetal villus were devoid of RLF transcripts. Pseudostratified trophoblast cells at the base of fetal villi coexpressed RLF mRNA and immunoreactive MHC class Ib molecules. | ||||
| Phenotypes |
PCO (polycystic ovarian syndrome) POF (premature ovarian failure) |
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| Mutations |
3 mutations
Species: mouse
Species: human
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | July 22, 1999, midnight | by: |
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| last update: | Oct. 19, 2020, 1:34 p.m. | by: | hsueh email: |
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