AMH/MIS: what we know already about the gene, the protein and its regulation
Introduction
The existence of anti-Müllerian hormone (AMH), also known as Müllerian inhibiting substance (MIS) was first suggested by the pioneering experiments performed by the French scientist Alfred Jost in the 1940s. At the early stages of development in mammals, foetuses of both sexes have two pairs of ducts: the mesonephric or Wolffian ducts and the paramesonephric or Müllerian ducts. In the male foetus, the development of Wolffian ducts into the epididymes, vasa deferentia and seminal vesicles was already known to occur under the influence of testicular androgens. Jost had noticed that a crystal of testosterone propionate was capable of masculinising Wolffian ducts in the female foetus but it did not affect Müllerian ducts, which formed the Fallopian tubes, the uterus and the upper third of the vagina. Intrigued by this observation, Jost developed refined techniques of foetal surgery allowing him to show that a testicular product different from testosterone, that he named “hormone inhibitrice” or “Müllerian inhibitor”, was responsible for the regression of Müllerian ducts in the male foetus (Jost, 1953).
The identification of the “Müllerian inhibitor” did not prove easy. In 1969, one of Jost’s pupils, Régine Picon, developed a test for the detection of anti-Müllerian activity (Picon, 1969). In 1972, another disciple of Jost’s, Nathalie Josso, showed the macromolecular nature of AMH (Josso, 1972), and in 1978, the first evidence was produced indicating its glycoprotein dimeric nature (Picard et al., 1978). Picon’s test, as well as antibodies developed by a third former member of Jost’s laboratory, Bernard Vigier (Vigier et al., 1982), and by Patricia Donahoe’s team in Boston (Mudgett-Hunter et al., 1982, Shima et al., 1984), helped to localise AMH activity to immature Sertoli cells (Josso, 1973; Donahoe et al., 1976, Donahoe et al., 1977a, Donahoe et al., 1977b; Tran et al., 1977, Tran and Josso, 1982, Hayashi et al., 1984) and to granulosa cells of the postnatal ovary (Vigier et al., 1984, Takahashi et al., 1986). Different strategies were subsequently used in Paris (Picard and Josso, 1980) and Boston (Budzik et al., 1980, Budzik et al., 1983) until AMH could be purified to homogeneity by immunochromatography in 1984 (Picard and Josso, 1984). Finally in 1986, some three decades after Jost first suggested the existence of the “Müllerian inhibitor”, the human and bovine genes for AMH/MIS were isolated and sequenced by Richard Cate in Boston (Cate et al., 1986), while the bovine cDNA was cloned by Jean-Yves Picard in Paris (Picard et al., 1986a). This was the beginning of the “recombinant-protein age” in AMH history, characterised by a rapid increase in the knowledge of its biological effects and mechanisms of action, as well as of its normal and pathological expression and the regulatory mechanisms involved. In 1994, the AMH signalling pathway began to be unravelled when the specific AMH receptor type II was cloned (di Clemente et al., 1994, Baarends et al., 1994). This specific AMH receptor is present on the cell membrane and is responsible for ligand binding. It subsequently recruits a type I receptor in order to transduce its signal. Three different type I receptors are considered to mediate AMH response in target cells: ALK6, named BMPRI-B (Gouédard et al., 2000), ALK2, named ActRI (Visser et al., 2001, Clarke et al., 2001), and ALK3, also known as BMPRI-A (Jamin et al., 2002). The intracellular transduction pathways involved after type I receptor recruitment by the specific type II AMH receptor seem to vary according to the target cell (reviewed by Josso and di Clemente, 2003).
Section snippets
The protein and the gene
For practical reasons, AMH was first purified from new-born calf testes (Picard and Josso, 1984, Shima et al., 1984, Picard et al., 1986b). Cloning of the human gene (Cate et al., 1986) allowed the use of recombinant DNA techniques to obtain recombinant human AMH in Chinese hamster ovary (CHO) cells (Wallen et al., 1989, Stephen et al., 2001). The highly conserved AMH molecules are 140 kDa dimeric glycoproteins (Picard et al., 1978, Budzik et al., 1980); following cleavage of disulfide bonds by
In the mammalian foetus
AMH has been named after its first described function in foetal sex differentiation, where the effect of AMH is unique as can be concluded from the phenotype resulting from AMH or AMH receptor mutations in humans (Belville et al., 1999) or from transgenic manipulation in mice (Behringer et al., 1990, Behringer et al., 1994, Mishina et al., 1996). Müllerian ducts are present and the specific AMH receptor is expressed in the foetuses of both sexes at the time when sexual differentiation is
AMH/MIS in the ovary
Ovarian granulosa cells, the homologous to testicular Sertoli cells, also produce AMH (Vigier et al., 1984) but with several differences: AMH expression only begins at the peri-natal period (Bezard et al., 1987, Ueno et al., 1989, Rajpert-De Meyts et al., 1999), remains low throughout reproductive life and becomes undetectable after menopause (Rey et al., 1996a, Lee et al., 1996). Granulosa cells of primary and small cavitary follicles show homogeneous AMH expression, in larger follicles, AMH
AMH/MIS in non-mammalian species
AMH has also been studied in birds and reptiles. Chick AMH has interspecific activity in birds and is also active on mammalian Müllerian ducts. Conversely, mammalian AMH is inactive in the chick (Tran and Josso, 1977, Hutson and Donahoe, 1983). Chick AMH shows 25–50% amino acid conservation when compared with mammalian AMH proteins, with the C-terminus as the most conserved fragment (reviewed by Carré-Eusèbe et al., 1997). The 4.2 kbp gene encoding chick AMH is organised in five exons (
Concluding remarks
The pioneering work done by Jost, first suggested the existence of AMH more than 50 years ago. Thereafter, the biochemistry and molecular biology eras of AMH research have progressively improved our knowledge of the protein, the gene, its expression and the regulatory mechanisms involved. The continual development of new technical tools has also allowed to apply the information obtained from basic science to the understanding and diagnosis of paediatric and reproductive disorders. More
Acknowledgements
Rodolfo Rey and Celina Lasala are recipients of grants from the Ministerio de Salud de la Nación (Beca Oñativia-Carrillo) and the Fundación Antorchas (grant no. 14116-189), Argentina.
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Present address: Service d’Endocrinologie et Maladies Métaboliques, Centre Hospitalier Universitaire, Reims, France.