Gene Symbol: Insl3
Description: insulin-like 3
Alias: Rlf, Rlnl, insulin-like 3, Ley I-L, ley-I-L, leydig insulin-like peptide, relaxin-like factor
Species: mouse
Products:     Insl3

Top Publications

  1. Robert N, Martin L, Tremblay J. The orphan nuclear receptor NR4A1 regulates insulin-like 3 gene transcription in Leydig cells. Biol Reprod. 2006;74:322-30 pubmed
    Insulin-like 3 (INSL3) is a hormone produced by fetal and adult Leydig cells of the testis and by theca and luteal cells of the adult ovary...
  2. Warr N, Siggers P, Bogani D, Brixey R, Pastorelli L, Yates L, et al. Sfrp1 and Sfrp2 are required for normal male sexual development in mice. Dev Biol. 2009;326:273-84 pubmed publisher
    ..of double homozygotes are smaller than controls, contain fewer cords from the earliest stages, but still express Insl3, which encodes the hormone required for gubernacular masculinisation...
  3. Barsoum I, Bingham N, Parker K, Jorgensen J, Yao H. Activation of the Hedgehog pathway in the mouse fetal ovary leads to ectopic appearance of fetal Leydig cells and female pseudohermaphroditism. Dev Biol. 2009;329:96-103 pubmed publisher
    ..This study provides not only insights into mechanisms of cell lineage specification in gonads, but also a model to understand defects in sexual differentiation. ..
  4. Zimmermann S, Steding G, Emmen J, Brinkmann A, Nayernia K, Holstein A, et al. Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol. 1999;13:681-91 pubmed
    ..The Insl3 gene (originally designated Ley I-L), a member of the insulin-like superfamily, is specifically expressed in ..
  5. Laguë E, Tremblay J. Estradiol represses insulin-like 3 expression and promoter activity in MA-10 Leydig cells. Toxicology. 2009;258:101-5 pubmed publisher
    ..the estrogen receptor alpha (ERalpha), have been shown to repress expression of the gene encoding insulin-like 3 (INSL3), a small peptide produced by testicular Leydig cells that is essential for normal testis descent...
  6. Spanel Borowski K, Schafer I, Zimmermann S, Engel W, Adham I. Increase in final stages of follicular atresia and premature decay of corpora lutea in Insl3-deficient mice. Mol Reprod Dev. 2001;58:281-6 pubmed
    The insulin-like factor 3 (Insl3), a member of the insulin-like hormone family, is exclusively synthesized in gonads...
  7. Miyabayashi K, Katoh Fukui Y, Ogawa H, Baba T, Shima Y, Sugiyama N, et al. Aristaless related homeobox gene, Arx, is implicated in mouse fetal Leydig cell differentiation possibly through expressing in the progenitor cells. PLoS ONE. 2013;8:e68050 pubmed publisher
    ..Based on these results, we propose that ARX acts as a positive factor for differentiation of fetal Leydig cells through functioning at the progenitor stage. ..
  8. Pusch W, Balvers M, Ivell R. Molecular cloning and expression of the relaxin-like factor from the mouse testis. Endocrinology. 1996;137:3009-13 pubmed
  9. Feng S, Bogatcheva N, Kamat A, Truong A, Agoulnik A. Endocrine effects of relaxin overexpression in mice. Endocrinology. 2006;147:407-14 pubmed
    ..Transgenic overexpression of Rln1 did not rescue the undescended testis phenotype in Insl3-deficient males, suggesting that in vivo relaxin does not interact with the insulin-like 3 factor receptor, ..

More Information


  1. Hombach Klonisch S, Bialek J, Radestock Y, Truong A, Agoulnik A, Fiebig B, et al. INSL3 has tumor-promoting activity in thyroid cancer. Int J Cancer. 2010;127:521-31 pubmed publisher
    The functional role of INSL3 and its receptor RXFP2 in carcinogenesis is largely unknown...
  2. Kaftanovskaya E, Feng S, Huang Z, Tan Y, Barbara A, Kaur S, et al. Suppression of insulin-like3 receptor reveals the role of ?-catenin and Notch signaling in gubernaculum development. Mol Endocrinol. 2011;25:170-83 pubmed publisher
    ..The first stage of testicular descent is controlled by insulin like3 hormone (INSL3), produced in testicular Leydig cells. Deletion of Insl3 or its receptor, Rxfp2, in mice causes cryptorchidism...
  3. Siggers P, Carré G, Bogani D, Warr N, Wells S, Hilton H, et al. A novel mouse Fgfr2 mutant, hobbyhorse (hob), exhibits complete XY gonadal sex reversal. PLoS ONE. 2014;9:e100447 pubmed publisher
    ..We exploited the consistent phenotype of this constitutive mutant by analysing MAPK signalling at the sex-determining stage of gonad development, but no significant abnormalities in mutant embryos were detected. ..
  4. Emmen J, McLuskey A, Adham I, Engel W, Verhoef Post M, Themmen A, et al. Involvement of insulin-like factor 3 (Insl3) in diethylstilbestrol-induced cryptorchidism. Endocrinology. 2000;141:846-9 pubmed
    Recently, it has been shown that targeted inactivation of the Insl3 gene in male mice results in cryptorchidism. The Insl3 gene encodes insulin-like factor 3 (Insl3), which is expressed in fetal Leydig cells...
  5. Schillebeeckx M, Pihlajoki M, Gretzinger E, Yang W, Thol F, Hiller T, et al. Novel markers of gonadectomy-induced adrenocortical neoplasia in the mouse and ferret. Mol Cell Endocrinol. 2015;399:122-30 pubmed publisher
    ..intact mice demonstrated selective upregulation of gonadal-like genes including Spinlw1 and Insl3 in GDX-induced adrenocortical tumors of the mouse...
  6. Adham I, Steding G, Thamm T, Bullesbach E, Schwabe C, Paprotta I, et al. The overexpression of the insl3 in female mice causes descent of the ovaries. Mol Endocrinol. 2002;16:244-52 pubmed
    ..upon proper outgrowth of the gubernaculum primordia under the influence of the insulin-like 3 gene product (Insl3). Deletion of this gene prevents gubernaculum growth and causes bilateral cryptorchidism...
  7. Huang Z, Kaftanovskaya E, Rivas B, Agoulnik A. Mechanisms of INSL3 signaling in male reproductive organs. Ital J Anat Embryol. 2013;118:32-3 pubmed
    Global ablation of INSL3 hormone or its receptor RXFP2 in male mice results in cryptorchidism and infertility. Using novel LacZ knock-in Rxfp2 allele we demonstrated a strong expression of this gene in postmeiotic germ cells...
  8. Chawengsaksophak K, Svingen T, Ng E, Epp T, Spiller C, Clark C, et al. Loss of Wnt5a disrupts primordial germ cell migration and male sexual development in mice. Biol Reprod. 2012;86:1-12 pubmed publisher
    ..testicular hypoplasia and bilateral cryptorchidism despite the Leydig cells producing factors such as Hsd3b1 and Insl3. Additionally, Wnt5a-null embryos of both sexes showed a significant reduction in gonadal germ cell numbers, which ..
  9. Kubota Y, Nef S, Farmer P, Temelcos C, Parada L, Hutson J. Leydig insulin-like hormone, gubernacular development and testicular descent. J Urol. 2001;165:1673-5 pubmed
    ..Recently, a mouse mutant for Leydig insulin-like hormone (Insl3) was found to have undescended testis and deficient gubernaculum...
  10. Tomiyama H, Hutson J, Truong A, Agoulnik A. Transabdominal testicular descent is disrupted in mice with deletion of insulinlike factor 3 receptor. J Pediatr Surg. 2003;38:1793-8 pubmed
    Several factors are implicated in transabdominal testicular descent, including insulinlike factor 3 (INSL3) hormone and Müllerian-inhibiting substance (MIS)...
  11. Roberts L, Shen J, Ingraham H. New solutions to an ancient riddle: defining the differences between Adam and Eve. Am J Hum Genet. 1999;65:933-42 pubmed
  12. Dev A, Nayernia K, Meins M, Adham I, Lacone F, Engel W. Mice deficient for RNA-binding protein brunol1 show reduction of spermatogenesis but are fertile. Mol Reprod Dev. 2007;74:1456-64 pubmed
    ..An intensive phenotypic analysis showed no gross abnormalities in testis morphology. Collectively our results demonstrate that Brunol1 might be nonessential protein for mouse embryonic development and spermatogenesis. ..
  13. Duan S, Zhang X, Jiang X, Xie L, Sun Z, Ma S, et al. An insight into insulin-like factor 3 regulate its receptor RXFP2 in mouse gubernaculum testis cells. Int J Clin Exp Pathol. 2015;8:14806-11 pubmed
    ..that the abnormal development of the gubernaculum may affect testicular descent, and the insulin-like factor 3 (INSL3) appears to play an important role in development of the gubernaculum have been proved...
  14. Zimmermann S, Schöttler P, Engel W, Adham I. Mouse Leydig insulin-like (Ley I-L) gene: structure and expression during testis and ovary development. Mol Reprod Dev. 1997;47:30-8 pubmed
    ..In the ovary, the expression of Ley I-L was first detected at day 6 after birth. The pattern of Ley I-L expression at various stages of the estrous cycle and during pregnancy showed a correlation with follicle development. ..
  15. Liu C, Bingham N, Parker K, Yao H. Sex-specific roles of beta-catenin in mouse gonadal development. Hum Mol Genet. 2009;18:405-17 pubmed publisher
    ..Our results demonstrate that beta-catenin is responsible for transducing sex-specific signals in the SF1-positive somatic cell population during mouse gonadal development. ..
  16. Burnicka Turek O, Shirneshan K, Paprotta I, Grzmil P, Meinhardt A, Engel W, et al. Inactivation of insulin-like factor 6 disrupts the progression of spermatogenesis at late meiotic prophase. Endocrinology. 2009;150:4348-57 pubmed publisher
    ..These results demonstrate that INSL6 is required for the progression of spermatogenesis. ..
  17. Vanhoutteghem A, Messiaen S, Hervé F, Delhomme B, Moison D, Petit J, et al. The zinc-finger protein basonuclin 2 is required for proper mitotic arrest, prevention of premature meiotic initiation and meiotic progression in mouse male germ cells. Development. 2014;141:4298-310 pubmed publisher
    ..In view of the extreme evolutionary conservation of BNC2, the findings described here are likely to apply to many species. ..
  18. Adham I, Khulan J, Held T, Schmidt B, Meyer B, Meinhardt A, et al. Fas-associated factor (FAF1) is required for the early cleavage-stages of mouse embryo. Mol Hum Reprod. 2008;14:207-13 pubmed publisher
    ..Thus, our results indicate that the FAF1 gene product is necessary for early embryonic development. ..
  19. Koskimies P, Spiess A, Lahti P, Huhtaniemi I, Ivell R. The mouse relaxin-like factor gene and its promoter are located within the 3' region of the JAK3 genomic sequence. FEBS Lett. 1997;419:186-90 pubmed
    Isolation and sequencing of a genomic clone encoding the mouse gene for the relaxin-like factor (RLF), which is endogenously expressed to a high level exclusively in Leydig cells, indicated that similar sequences were also present at the ..
  20. Feng S, Bogatcheva N, Kamat A, Agoulnik A. Genetic targeting of relaxin and insl3 signaling in mice. Ann N Y Acad Sci. 2005;1041:82-90 pubmed
    We studied ligand-receptor interactions between relaxin (RLN), insulin-like 3 peptide (INSL3), and LGR7 and LGR8 receptors...
  21. Nef S, Parada L. Cryptorchidism in mice mutant for Insl3. Nat Genet. 1999;22:295-9 pubmed
    ..Leydig insulin-like hormone (Insl3) is a member of the insulin hormone superfamily expressed in the developing testis...
  22. Koskimies P, Levallet J, Sipila P, Huhtaniemi I, Poutanen M. Murine relaxin-like factor promoter: functional characterization and regulation by transcription factors steroidogenic factor 1 and DAX-1. Endocrinology. 2002;143:909-19 pubmed
    The gene for mouse relaxin-like factor (RLF), a member of the insulin/IGF/relaxin family of hormones, appears to be predominantly expressed in testicular Leydig cells...
  23. Miyado M, Nakamura M, Miyado K, Morohashi K, Sano S, Nagata E, et al. Mamld1 deficiency significantly reduces mRNA expression levels of multiple genes expressed in mouse fetal Leydig cells but permits normal genital and reproductive development. Endocrinology. 2012;153:6033-40 pubmed publisher
    ..mRNA levels (65-80%) of genes exclusively expressed in Leydig cells (Star, Cyp11a1, Cyp17a1, Hsd3b1, and Insl3) as well as grossly normal testicular mRNA levels of genes expressed in other cell types or in Leydig and other ..
  24. Shawki H, Oishi H, Usui T, Kitadate Y, Basha W, Abdellatif A, et al. MAFB is dispensable for the fetal testis morphogenesis and the maintenance of spermatogenesis in adult mice. PLoS ONE. 2018;13:e0190800 pubmed publisher
  25. Nicol B, Yao H. Gonadal Identity in the Absence of Pro-Testis Factor SOX9 and Pro-Ovary Factor Beta-Catenin in Mice. Biol Reprod. 2015;93:35 pubmed publisher
    ..Our findings not only provide insight into the mechanism of sex determination, but also identify candidate genes that are potentially involved in disorders of sex development. ..
  26. Tevosian S, Jiménez E, Hatch H, Jiang T, Morse D, Fox S, et al. Adrenal Development in Mice Requires GATA4 and GATA6 Transcription Factors. Endocrinology. 2015;156:2503-17 pubmed publisher
    ..Our results reveal a requirement for GATA factors in adrenal development and provide a novel tool to characterize the transcriptional network controlling adrenocortical cell fates. ..
  27. Spiess A, Balvers M, Tena Sempere M, Huhtaniemi I, Parry L, Ivell R. Structure and expression of the rat relaxin-like factor (RLF) gene. Mol Reprod Dev. 1999;54:319-25 pubmed
    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 ..
  28. Ricci G, Guglielmo M, Caruso M, Ferranti F, Canipari R, Galdieri M, et al. Hepatocyte growth factor is a mouse fetal Leydig cell terminal differentiation factor. Biol Reprod. 2012;87:146 pubmed publisher
    ..fragment; 2) HGF does not affect FLC proliferation; 3) HGF significantly increases expression of insulin-like 3 (INSL3), a marker of Leydig cell terminal differentiation, without affecting 3beta-hydroxysteroid dehydrogenase (3betaHSD)..
  29. Koskimies P, Suvanto M, Nokkala E, Huhtaniemi I, McLuskey A, Themmen A, et al. Female mice carrying a ubiquitin promoter-Insl3 transgene have descended ovaries and inguinal hernias but normal fertility. Mol Cell Endocrinol. 2003;206:159-66 pubmed
    Mouse knockout studies have indicated that Insl3 is involved in development of the gubernaculum in males, which is essential for normal testicular descent...
  30. Held T, Barakat A, Mohamed B, Paprotta I, Meinhardt A, Engel W, et al. Heat-shock protein HSPA4 is required for progression of spermatogenesis. Reproduction. 2011;142:133-44 pubmed publisher
    ..These results provide evidence that HSPA4 is required for normal spermatogenesis. ..
  31. Kamat A, Feng S, Bogatcheva N, Truong A, Bishop C, Agoulnik A. Genetic targeting of relaxin and insulin-like factor 3 receptors in mice. Endocrinology. 2004;145:4712-20 pubmed
    ..Transgenic overexpression of Insl3, the cognate ligand for Lgr8, does not rescue the mutant phenotype of Lgr7-deficient female mice indicating ..
  32. Sarraj M, Escalona R, Umbers A, Chua H, Small C, Griswold M, et al. Fetal testis dysgenesis and compromised Leydig cell function in Tgfbr3 (beta glycan) knockout mice. Biol Reprod. 2010;82:153-62 pubmed publisher
    ..The expression levels of the Leydig cell markers Insl3, Cyp17a1, Cyp11a1, Star, and Hsd3b1 were reduced in knockout testis compared to wild-type testis, beginning at 12...
  33. Song X, Wei G, Liu X, Zhang D, Chen X, Deng Y. Effects of diethylhexyl phthalate (DEHP) on INSL3 mRNA expression by Leydig cells derived from mouse embryos and in newborn mice. J Int Med Res. 2008;36:512-21 pubmed
    Insulin-like factor 3 (INSL3) regulates testicular descent during fetal life, and Insl3 gene inactivation results in cryptorchidism...
  34. Huang Z, Rivas B, Agoulnik A. Insulin-like 3 signaling is important for testicular descent but dispensable for spermatogenesis and germ cell survival in adult mice. Biol Reprod. 2012;87:143 pubmed publisher
    Relaxin family peptide receptor 2 (RXFP2) is the cognate receptor of a peptide hormone insulin-like 3 (INSL3). INSL3 is expressed at high levels in both fetal and adult Leydig cells...
  35. Buaas F, Gardiner J, Clayton S, Val P, Swain A. In vivo evidence for the crucial role of SF1 in steroid-producing cells of the testis, ovary and adrenal gland. Development. 2012;139:4561-70 pubmed publisher
    ..This study is the first to show the in vivo requirements of SF1 in steroidogenesis and provides novel data on the cellular consequences of the loss of this protein specifically within steroid-producing cells. ..
  36. Bogatcheva N, Truong A, Feng S, Engel W, Adham I, Agoulnik A. GREAT/LGR8 is the only receptor for insulin-like 3 peptide. Mol Endocrinol. 2003;17:2639-46 pubmed
    ..Two genes, encoding the insulin-like 3 peptide (INSL3) and the GREAT/LGR8 G protein-coupled receptor, control the differentiation of gubernaculum, the caudal ..
  37. Nef S, Verma Kurvari S, Merenmies J, Vassalli J, Efstratiadis A, Accili D, et al. Testis determination requires insulin receptor family function in mice. Nature. 2003;426:291-5 pubmed
    ..Reduced expression of both Sry and the early testis-specific marker Sox9 indicates that the insulin signalling pathway is required for male sex determination. ..
  38. Mendoza Villarroel R, Di Luoffo M, Camiré E, Giner X, Brousseau C, Tremblay J. The INSL3 gene is a direct target for the orphan nuclear receptor, COUP-TFII, in Leydig cells. J Mol Endocrinol. 2014;53:43-55 pubmed publisher
    Insulin-like 3 (INSL3), a hormone produced by Leydig cells, regulates testicular descent during foetal life and bone metabolism in adults...
  39. Adham I, Emmen J, Engel W. The role of the testicular factor INSL3 in establishing the gonadal position. Mol Cell Endocrinol. 2000;160:11-6 pubmed
    b>INSL3, also designated Leydig insulin-like (Ley I-L) or relaxin-like factor (RLF), belongs to the insulin-like hormone superfamily...
  40. Sozubir S, Barber T, Wang Y, Ahn C, Zhang S, Verma S, et al. Loss of Insl3: a potential predisposing factor for testicular torsion. J Urol. 2010;183:2373-9 pubmed publisher
    The testicular hormone Insl3 is critical for mouse gubernacular development. Knockout mice exhibit bilateral intra-abdominal cryptorchidism with absent gubernaculum...
  41. Val P, Jeays Ward K, Swain A. Identification of a novel population of adrenal-like cells in the mammalian testis. Dev Biol. 2006;299:250-6 pubmed
    ..These cells also express Cyp17 and respond to hCG stimulation but do not express the Leydig specific marker Insl3 showing that they are a population of steroidogenic cells distinct from Leydig cells...
  42. Anand Ivell R, Heng K, Hafen B, Setchell B, Ivell R. Dynamics of INSL3 peptide expression in the rodent testis. Biol Reprod. 2009;81:480-7 pubmed publisher
    The Leydig cell-specific factor insulin-like peptide 3 (INSL3) is involved in testicular descent during embryo development, and has been suggested to regulate spermatogenesis and bone metabolism in the adult...
  43. Laguë E, Tremblay J. Antagonistic effects of testosterone and the endocrine disruptor mono-(2-ethylhexyl) phthalate on INSL3 transcription in Leydig cells. Endocrinology. 2008;149:4688-94 pubmed publisher
    Insulin-like 3 (INSL3) is a small peptide produced by testicular Leydig cells throughout embryonic and postnatal life and by theca and luteal cells of the adult ovary...