Müllerian inhibiting substance as oocyte meiosis inhibitor

Takahashi, Masahiko; Koide, S. S.; Donahoe, Patricia K.

doi:10.1016/0303-7207(86)90116-4

Cited by 114 publications

(45 citation statements)

References 54 publications

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“…Additionally, although the lyase activity in mice appears to be greater than the hydroxylase activity (27), the opposite may be true in rats (28). Another example of MIS affecting mouse and rat physiology differently was the observation that MIS could inhibit oocyte meiosis in rats but not in mice (29)(30)(31). In mice, a low molecular weight cAMP-dependent protein found in follicular fluid, oocyte maturation inhibitor, accomplishes this function (29).…”

Section: Resultsmentioning

confidence: 99%

Müllerian Inhibiting Substance lowers testosterone in luteinizing hormone-stimulated rodents

Trbovich

Sluss

Laurich

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Mü llerian Inhibiting Substance (MIS) expression is inversely proportional to the serum concentration of testosterone in males after birth and in vitro studies have shown that MIS can lower testosterone production by Leydig cells. Also, mice overexpressing MIS exhibited Leydig cell hypoplasia and lower levels of serum testosterone, but it is not clear whether this is a result of MIS affecting the development of Leydig cells or their capacity to produce testosterone. To examine the hypothesis that MIS treatment will result in decreased testosterone production by mature Leydig cells in vivo, we treated luteinizing hormone (LH)-stimulated adult male rats and mice with MIS and demonstrated that it can lead to a several-fold reduction in testosterone in serum and in testicular extracts. There was also a slight decrease in 17-OH-progesterone compared to the more significant decrease in testosterone, suggesting that MIS might be regulating the lyase activity of cytochrome P450c17 hydroxylase͞lyase (Cyp17), but not its hydroxylase activity. Northern analysis showed that, in both MIS-treated rats and mice, the mRNA for Cyp17, which catalyzes the committed step in androgen synthesis, was down-regulated. In rats, the mRNA for cytochrome P450 side-chain cleavage (P450scc) was also downregulated by MIS. This was not observed in mice, indicating that there might be species-specific regulation by MIS of the enzymes involved in the testosterone biosynthetic pathway. Our results show that MIS can be used in vivo to lower testosterone production by mature rodent Leydig cells and suggest that MIS-mediated down-regulation of the expression of Cyp17, and perhaps P450scc, contributes to that effect.

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Section: Resultsmentioning

confidence: 99%

Müllerian Inhibiting Substance lowers testosterone in luteinizing hormone-stimulated rodents

Trbovich

Sluss

Laurich

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…4c,d). This is of note because MIS expression by granulosa cells of the cycling rat ovary is greatest in preantral and antral follicles prior to ovulation, particularly in the cell layers closest to the oocyte (Ueno et al, 1989), and because MIS has been shown to inhibit oocyte meiosis in vitro (Takahashi et al, 1986). Again, such signal localization is suggestive that R1 is a candidate MIS receptor.…”

Section: Developmental Expression Of Rl-r4 Mrnamentioning

confidence: 92%

Developmental expression of four novel serine/threonine kinase receptors homologous to the activin/transforming growth factor‐β type II receptor family

Gustafson

Hirobe

et al. 1993

Developmental Dynamics

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164

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Serinekhreonine kinase transmembrane proteins are a new family of growth factor signal transducers that includes several isoforms of the activin type I1 receptor and the type I1 receptor for transforming growth factor-p. In an effort to clone the receptor for Mullerian inhibiting substance, a member of the transforming growth factor-p superfamily, oligonucleotide primers designed from conserved regions of these receptors' kinase domains were used for PCR amplification of fetal rat urogenital ridge cDNA. We isolated four novel receptors in this manner (designated Rl-R4), each of which has structural features of the previously cloned kinases, including a small extracellular ligand-binding domain, a single hydrophobic transmembrane domain, and an intracellular serinekhreonine kinase domain. In addition, each has characteristic kinase subdomains and conserved serinekhreonine kinase sequences found in this family. Northern analysis revealed mRNA expression of R1-R4 in several tissues, including fetal urogenital ridge, testis, and ovary, as well as brain and lung. In situ hybridization further localized R1 to mesenchyme of the 14.5 to 15-day fetal rat Mullerian duct and to oocytes of preantral and antral follicles, sites that are consistent with the predicted localization of Mullerian inhibiting substance receptor. In addition, R2 localized specifically to seminiferous tubules of the postnatal testis. These newest members of the activin and transforming growth factor-p type I1 receptor family should help define the molecular mechanisms by which this ligand superfamily affects cell growth and differentiation via membrane phosphorylation.

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“…S2A). Reports of the effect of MIS on follicles have been mixed, with some studies suggesting an activating effect (45,46) and others implying a direct inhibitory effect (18,47), indirect inhibition via gonadotropins (48,49), or even regulation of meiosis (50). In past studies, the magnitude of inhibition of primordial follicle recruitment in vivo and in vitro has been perceived as relatively modest because of difficulties in achieving high concentrations of the protein.…”

Section: Discussionmentioning

confidence: 99%

AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy

Kano

Sosulski

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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163

171

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The ovarian reserve represents the stock of quiescent primordial follicles in the ovary which is gradually depleted during a woman's reproductive lifespan, resulting in menopause. Müllerian inhibiting substance (MIS) (or anti-Müllerian hormone/AMH), which is produced by granulosa cells of growing follicles, has been proposed as a negative regulator of primordial follicle activation. Here we show that long-term parenteral administration of superphysiological doses of MIS, using either an adeno-associated virus serotype 9 (AAV9) gene therapy vector or recombinant protein, resulted in a complete arrest of folliculogenesis in mice. The ovaries of MIS-treated mice were smaller than those in controls and did not contain growing follicles but retained a normal ovarian reserve. When mice treated with AAV9/MIS were paired with male breeders, they exhibited complete and permanent contraception for their entire reproductive lifespan, disrupted vaginal cycling, and hypergonadotropic hypogonadism. However, when ovaries from AAV9-MIS-treated mice were transplanted orthotopically into normal recipient mice, or when treatment with the protein was discontinued, folliculogenesis resumed, suggesting reversibility. One of the important causes of primary ovarian insufficiency is chemotherapy-induced primordial follicle depletion, which has been proposed to be mediated in part by increased activation. To test the hypothesis that MIS could prevent chemotherapy-induced overactivation, mice were given carboplatin, doxorubicin, or cyclophosphamide and were cotreated with AAV9-MIS, recombinant MIS protein, or vehicle controls. We found significantly more primordial follicles in MIS-treated animals than in controls. Thus treatment with MIS may provide a method of contraception with the unique characteristic of blocking primordial follicle activation that could be exploited to prevent the primary ovarian insufficiency often associated with chemotherapy.M üllerian inhibiting substance (MIS), also known as antiMüllerian hormone (AMH), has long been appreciated for its role in sex differentiation and reproduction, and sensitive ELISAs measuring blood levels are used in fertility clinics around the world as a measure of ovarian reserve (1-6). MIS plays important roles in the development of the gonad and the differentiation of the urogenital ridge. In the male fetus, MIS produced by the developing testes causes regression of the Müllerian duct (7). In the female fetus, MIS may play a role in early follicle assembly in the gonad by primordial germ cells (not to be confused with primordial follicles), since mice overexpressing MIS are devoid of germ cells shortly after birth (8), and, similarly, ex vivo incubation of fetal ovaries with MIS results in the inhibition of follicle assembly (9). These data highlight a role of MIS during fetal development that is distinct from its regulatory role of folliculogenesis postnatally.In the adult, MIS is produced predominantly by the cumulus (less so by the mural) granulosa cells of secondary and early antral...

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Müllerian inhibiting substance as oocyte meiosis inhibitor

Cited by 114 publications

References 54 publications

Müllerian Inhibiting Substance lowers testosterone in luteinizing hormone-stimulated rodents

Müllerian Inhibiting Substance lowers testosterone in luteinizing hormone-stimulated rodents

Developmental expression of four novel serine/threonine kinase receptors homologous to the activin/transforming growth factor‐β type II receptor family

AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy

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