Home LiteratureArticle Details
PMID: 9435237 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Receptors for anti-müllerian hormone on Leydig cells are responsible for its effects on steroidogenesis and cell differentiation.

Racine C, Rey R, Forest MG, Louis F, Ferré A, Huhtaniemi I, Josso N, di Clemente N

Abstract

Strong overexpression of anti-Müllerian hormone (AMH) in transgenic mice leads to incomplete fetal virilization and decreased serum testosterone in the adult. Conversely, AMH-deficient mice exhibit Leydig cell hyperplasia. To probe the mechanism of action of AMH on Leydig cell steroidogenesis, we have studied the expression of mRNA for steroidogenic proteins in vivo and in vitro and performed a morphometric analysis of testicular tissue in mice overexpressing the hormone. We show that overexpression of AMH in male transgenic mice blocks the differentiation of Leydig cell precursors. Expression of steroidogenic protein mRNAs, mainly cytochrome P450 17 alpha-hydroxylase/C17-20 lyase (P450c17), is decreased in transgenic mice overexpressing AMH and in AMH-treated purified Leydig cells. In contrast, transgenic mice in whom the AMH locus has been disrupted show increase expression of P450c17. In vitro, but not in vivo, AMH also decreases the expression of the luteinizing hormone receptor. The effect of AMH is explained by the presence of its receptor on Leydig cells. Our results provide insight into the action of AMH as a negative modulator of Leydig cell differentiation and function.

MeSH Terms
Animals Anti-Mullerian Hormone Cell Differentiation/physiology Cells, Cultured Gene Transfer Techniques Glycoproteins Growth Inhibitors/physiology Leydig Cells/cytology,physiology Male Mice Mice, Transgenic Receptors, Peptide/physiology Receptors, Transforming Growth Factor beta Signal Transduction Steroids/metabolism Testicular Hormones/physiology
Chemicals
Glycoproteins Growth Inhibitors Receptors, Peptide Receptors, Transforming Growth Factor beta Steroids Testicular Hormones anti-Mullerian hormone receptor Anti-Mullerian Hormone
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Racine C
Institut National de la Santé et de la Recherche Médicale, Ecole Normale Supérieure, Département de Biologie, Montrouge, France.
Rey R
Forest M G
Louis F
Ferré A
Huhtaniemi I
Josso N
di Clemente N
References (51)
51 references, click to expand
  1. The lutropin/choriogonadotropin receptor ... 4 years later.
    Endocr Rev. 1993 Jun;14(3):324-47 PMID: 8319598
  2. Gonadotropin-induced positive regulation of testicular luteinizing hormone receptors.
    Endocrinology. 1981 Jan;108(1):58-65 PMID: 6257491
  3. Rat seminiferous tubular culture medium contains a biological factor that inhibits Leydig cell steroidogenesis: its purification and mechanism of action.
    Mol Cell Endocrinol. 1994 Sep;104(2):213-27 PMID: 7988748
  4. Structural organization of the rat luteinizing hormone (LH) receptor gene.
    J Biol Chem. 1991 Jun 15;266(17):11355-9 PMID: 2040640
  5. Ontogeny of expression of the genes for steroidogenic enzymes P450 side-chain cleavage, 3 beta-hydroxysteroid dehydrogenase, P450 17 alpha-hydroxylase/C17-20 lyase, and P450 aromatase in fetal mouse gonads.
    Endocrinology. 1994 Jul;135(1):262-8 PMID: 8013361
  6. Synergistic effects of inhibins and müllerian-inhibiting substance on testicular tumorigenesis.
    Mol Endocrinol. 1995 Oct;9(10):1337-45 PMID: 8544842
  7. Müllerian-inhibiting substance function during mammalian sexual development.
    Cell. 1994 Nov 4;79(3):415-25 PMID: 7954809
  8. Antimüllerian hormone: new perspectives for a sexist molecule.
    Endocr Rev. 1986 Nov;7(4):421-33 PMID: 3536462
  9. Practical stereological methods for morphometric cytology.
    J Cell Biol. 1966 Jul;30(1):23-38 PMID: 5338131
  10. Hormonal and developmental regulation of the steroidogenic acute regulatory protein.
    Mol Endocrinol. 1995 Oct;9(10):1346-55 PMID: 8544843
  11. Mullerian inhibiting substance: a gonadal hormone with multiple functions.
    Endocr Rev. 1993 Apr;14(2):152-64 PMID: 8325249
  12. Hormonal regulation of proteins secreted by cultured pig Sertoli cells: characterization by two-dimensional polyacrylamide gel electrophoresis.
    Mol Cell Endocrinol. 1985 Dec;43(2-3):189-97 PMID: 3000852
  13. Variants of the anti-Müllerian hormone gene in a compound heterozygote with the persistent Müllerian duct syndrome and his family.
    Hum Genet. 1992 Dec;90(4):389-94 PMID: 1483695
  14. Inhibins, activins, their binding proteins and receptors: interactions underlying paracrine activity in the testis.
    Mol Cell Endocrinol. 1994 Apr;100(1-2):81-6 PMID: 8056163
  15. Development of a new Leydig cell population after the destruction of existing Leydig cells by ethane dimethane sulphonate in rats: an autoradiographic study.
    J Endocrinol. 1990 Aug;126(2):229-36 PMID: 2169521
  16. Hormonal and cellular regulation of Sertoli cell anti-Müllerian hormone production in the postnatal mouse.
    J Clin Invest. 1997 Sep 15;100(6):1335-43 PMID: 9294098
  17. Identification of a stimulator of steroid hormone synthesis isolated from testis.
    Science. 1995 Jun 16;268(5217):1609-12 PMID: 7777858
  18. Use of monoclonal antibody techniques to study the ontogeny of bovine anti-Müllerian hormone.
    J Reprod Fertil. 1983 Sep;69(1):207-14 PMID: 6350571
  19. The inhibitory effects of müllerian-inhibiting substance on epidermal growth factor induced proliferation and progesterone production of human granulosa-luteal cells.
    J Clin Endocrinol Metab. 1992 Sep;75(3):911-7 PMID: 1517385
  20. Fluctuations in plasma testosterone levels in adult male rats and mice.
    Endocrinology. 1973 Apr;92(4):1223-8 PMID: 4686318
  21. Isolation of the bovine and human genes for Müllerian inhibiting substance and expression of the human gene in animal cells.
    Cell. 1986 Jun 6;45(5):685-98 PMID: 3754790
  22. A novel member of the transmembrane serine/threonine kinase receptor family is specifically expressed in the gonads and in mesenchymal cells adjacent to the müllerian duct.
    Development. 1994 Jan;120(1):189-97 PMID: 8119126
  23. Signs of aging are apparent in the testis interstitium of Sprague Dawley rats at 6 months of age.
    Tissue Cell. 1995 Dec;27(6):689-99 PMID: 8578559
  24. Developmental expression of a candidate müllerian inhibiting substance type II receptor.
    Endocrinology. 1996 Jan;137(1):160-5 PMID: 8536608
  25. Primary structure of rabbit 18S ribosomal RNA determined by direct RNA sequence analysis.
    Nucleic Acids Res. 1984 Jun 11;12(11):4731-45 PMID: 6330682
  26. Cloning, expression, and alternative splicing of the receptor for anti-Müllerian hormone.
    Mol Endocrinol. 1994 Aug;8(8):1006-20 PMID: 7997230
  27. Morphometric study of the testicular interstitial tissue of the monkey Cebus apella during postnatal development.
    Tissue Cell. 1996 Feb;28(1):31-42 PMID: 8907726
  28. Metabolic clearance rate and blood production rate of testosterone and dihydrotestosterone in normal subjects, during pregnancy, and in hyperthyroidism.
    J Clin Invest. 1972 May;51(5):1226-34 PMID: 5020435
  29. Total and unbound testosterone levels in the newborn and in normal and hypogonadal children: use of a sensitive radioimmunoassay for testosterone.
    J Clin Endocrinol Metab. 1973 Jun;36(6):1132-42 PMID: 4735892
  30. Ontogeny of reproductive abnormalities induced by deregulation of anti-müllerian hormone expression in transgenic mice.
    Biol Reprod. 1995 Feb;52(2):444-54 PMID: 7711213
  31. The presence of müllerian inhibiting substance in human seminal plasma.
    Hum Reprod. 1996 Oct;11(10):2165-9 PMID: 8943523
  32. The roles of the nuclear receptor steroidogenic factor 1 in endocrine differentiation and development.
    Trends Endocrinol Metab. 1996 Aug;7(6):203-7 PMID: 18406748
  33. Regulation of gonadotropin receptors, gonadotropin responsiveness, and cell multiplication by somatomedin-C and insulin in cultured pig Leydig cells.
    J Cell Physiol. 1986 Nov;129(2):257-63 PMID: 3533962
  34. Alpha-inhibin is a tumour-suppressor gene with gonadal specificity in mice.
    Nature. 1992 Nov 26;360(6402):313-9 PMID: 1448148
  35. Is infancy a quiescent period of testicular development? Histological, morphometric, and functional study of the seminiferous tubules of the cebus monkey from birth to the end of puberty.
    J Clin Endocrinol Metab. 1993 May;76(5):1325-31 PMID: 8496325
  36. Maturational changes in steroidogenic enzyme activities metabolizing testosterone and dihydrotestosterone in two populations of testicular interstitial cells.
    Acta Endocrinol (Copenh). 1989 Oct;121(4):477-83 PMID: 2552727
  37. Genetic analysis of the Müllerian-inhibiting substance signal transduction pathway in mammalian sexual differentiation.
    Genes Dev. 1996 Oct 15;10(20):2577-87 PMID: 8895659
  38. Leydig cells: endocrine, paracrine, and autocrine regulation.
    Endocr Rev. 1994 Oct;15(5):574-626 PMID: 7843069
  39. The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR).
    J Biol Chem. 1994 Nov 11;269(45):28314-22 PMID: 7961770
  40. The testicular receptor for follicle stimulating hormone: structure and functional expression of cloned cDNA.
    Mol Endocrinol. 1990 Apr;4(4):525-30 PMID: 2126341
  41. Abnormal sexual development in transgenic mice chronically expressing müllerian inhibiting substance.
    Nature. 1990 May 10;345(6271):167-70 PMID: 2336108
  42. Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases.
    Mol Endocrinol. 1994 May;8(5):654-62 PMID: 8058073
  43. A supersensitive immunofluorometric assay for rat luteinizing hormone.
    Endocrinology. 1993 Apr;132(4):1687-91 PMID: 8462469
  44. The nucleotide sequence of the rat cytoplasmic beta-actin gene.
    Nucleic Acids Res. 1983 Mar 25;11(6):1759-71 PMID: 6300777
  45. Anti-müllerian hormone: the Jost factor.
    Recent Prog Horm Res. 1993;48:1-59 PMID: 8441845
  46. Insensitivity to anti-müllerian hormone due to a mutation in the human anti-müllerian hormone receptor.
    Nat Genet. 1995 Dec;11(4):382-8 PMID: 7493017
  47. Concentration of 14 steroid hormones in human amniotic fluid of midpregnancy.
    J Clin Endocrinol Metab. 1980 Oct;51(4):816-22 PMID: 7419668
  48. Mitochondrial specificity of the early steps in steroidogenesis.
    J Steroid Biochem Mol Biol. 1995 Dec;55(5-6):607-16 PMID: 8547188
  49. Freemartins in cattle: the first steps of sexual organogenesis.
    J Reprod Fertil. 1972 Jun;29(3):349-79 PMID: 5033926
  50. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease.
    Biochemistry. 1979 Nov 27;18(24):5294-9 PMID: 518835
  51. Postnatal development of testicular cell populations in mice.
    J Reprod Fertil. 1993 Nov;99(2):479-85 PMID: 8107030
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
Published
1998-01-20
Pages
594-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC18465
Subset
IM
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]