Disease relevance of Amh

• Mutations in mullerian inhibiting substance (MIS) or MISRII cause male sexual abnormalities, persistent mullerian duct syndrome, and pseudohermaphroditism [1].
• Collectively, these results suggest that in the absence of MIS, Leydig cells remain less differentiated, causing an altered intratesticular androgen milieu that may contribute to the infertility of MIS-KO mice [2].
• MIS knockout (MIS-KO) mice with targeted deletions of MIS develop Leydig cell hyperplasia, but their circulating androgen concentrations are reportedly unaltered [2].
• To extend the use of MIS to treat breast cancer, it is essential to test the responsiveness of mammary tumor growth to MIS in vivo [3].
• For example, breast and prostate cancer cell lines use a MIS-mediated NFkappaB pathway leading to G1 arrest and apoptosis [4].

High impact information on Amh

• These results identify Bmpr1a as a type I receptor for Amh-induced regression of Müllerian ducts [5].
• Mutations in AMH or AMHR2 in humans and mice disrupt signaling, producing male pseudohermaphrodites that possess oviducts and uteri [5].
• Male mice homozygous for the mutant SF1-binding site correctly initiated Mis transcription in fetal testes, although at significantly reduced levels [6].
• Surprisingly, sufficient MIS was produced to eliminate the MUllerian ducts [6].
• Targeted mutagenesis of the endogenous mouse Mis gene promoter: in vivo definition of genetic pathways of vertebrate sexual development [6].

Chemical compound and disease context of Amh

• Strong overexpression of anti-Müllerian hormone (AMH) in transgenic mice leads to incomplete fetal virilization and decreased serum testosterone in the adult [7].
• In the mouse, estrogen receptor-mediated mechanisms seem to be involved in induction of testicular tumors by prenatal estrogen exposure, and a direct, perhaps estrogen receptor-mediated, inhibiting effect of estrogens on the action of müllerian inhibiting substance is probably central in the induction of cryptorchidism in this species [8].
• CONCLUSIONS: Highly purified recombinant human MIS, delivered parenterally, or MIS produced endogenously causes inhibition of human ovarian cancer cell lines in vivo, providing convincing preclinical evidence to support the use of MIS as a parenteral agent for the treatment of ovarian cancer [9].

Biological context of Amh

• Expression of the Amh gene during sex differentiation requires the interaction of several transcription factors, including SF1, SOX9, GATA4, WT1, and DAX1 [10].
• Regulation of gonadotropin gene expression by Mullerian inhibiting substance [11].
• A panel of 78 backcross progeny, BALB/cJ x (BALB/cJ x CAST/Ei)F1, was used to map the gene encoding anti-Müllerian hormone (Amh), also called Müllerian inhibiting substance, to mouse Chromosome 10 (MMU10) [12].
• We conclude that AMH represents a useful marker of androgen and FSH action within the testis, as well as of the onset of meiosis [13].
• Mullerian inhibiting substance (MIS) inhibits breast cancer cell growth in vitro [3].

Anatomical context of Amh

• During an investigation of the regulatory potential of a region 5' of the mouse anti-müllerian hormone (Amh) gene, we identified a region of homology with the known cDNA sequence of a human spliceosome gene (SAP62) [14].
• Expression of Sox8 begins just prior to that of Amh at 12 days post coitum (dpc) in mouse testes and continues beyond 16 dpc in Sertoli cells [10].
• Recently, co-culture of isolated oocytes and granulosa cells has demonstrated that Amh expression is up-regulated in the presence of oocytes and, at preantral stages, this effect is dependent upon close contact [15].
• However, our studies involving the red-eared slider turtle indicate that Sox8 is expressed at similar levels in males and females throughout the sex-determining period, suggesting that Sox8 is neither a transcriptional regulator for Amh, nor responsible for sex determination or gonad differentiation in that species [16].
• Using LbetaT2 cells, a murine gonadotrope-derived cell line, we have evaluated the effects of MIS on the expression of the gonadotropin genes [11].

Associations of Amh with chemical compounds

• MIS is a member of the transforming growth factor-beta (TGFbeta) superfamily of secreted protein hormones that signal through receptor complexes of type I and type II serine/threonine kinase receptors [17].
• Ad4BP/SF-1, however, is also involved in the sex differentiation of the gonad at later stages, such as the regulation of steroid hormones and MIS [18].
• Clinical studies have demonstrated a negative correlation between serum AMH and testosterone in puberty but not in the neonatal period [13].
• We had shown previously that androgen-insensitive patients exhibit elevated AMH in coincidence with gonadotropin activation [13].
• Mullerian inhibiting substance (MIS) is a glycoprotein hormone expressed by Sertoli cells that induces the regression of Mullerian ducts during development of the male reproductive tract [19].

Physical interactions of Amh

• Furthermore DNA-protein interaction in in vitro studies showed first that GATA-1 binds with various affinities on sites found in the AMH promoter and second that the proximity of the two strongest affinity sites leads to a synergistic binding effect [20].

Regulatory relationships of Amh

• Addition of MIS to LbetaT2 cells stimulates the activity of the rat LHbeta gene promoter with as little as 1 microg/ml and in a dose-dependent manner [11].
• In mouse, Sox9 is expressed in the Sertoli cells of the embryonic testis and it precedes the onset of Amh expression [21].
• We hypothesized that the MIS-induced StAR expression is the indirect result of reduced testosterone synthesis in Leydig cells caused by MIS [22].
• Müllerian-inhibiting substance (MIS) reduces testosterone synthesis in Leydig cells by inhibiting cytochrome P450C17 hydroxylase/C17-20 lyase expression [22].
• In testes, the Wilms' tumor suppressor and the orphan nuclear receptor SF1 cooperatively bind to the promoter and activate transcription of MIS [23].

Other interactions of Amh

• These results allowed us to define a transitory 4-5-day period, starting from 3 dpp when both proteins are heterogeneously expressed in Sertoli cells and showed that the appearance of GATA-1 is associated with the decrease of AMH expression in these cells [20].
• Analysis of the role of Amh and Fra1 in the Sry regulatory pathway [24].
• Deficiency of MIS or of the MIS type II receptor, MISRII, results in abnormal reproductive development in the male due to the maintenance of the duct [17].
• ALK6 has been shown to function as an MIS type I receptor [17].
• The reporter construct analysis, pattern of expression of the receptors, and analysis of ALK6-deficient animals suggest that ALK2 is the MIS type I receptor involved in Müllerian duct regression [17].

Analytical, diagnostic and therapeutic context of Amh

• We cloned partial turtle Sox8 and anti-Müllerian hormone (Amh) cDNAs, and analyzed the expression patterns of these genes in developing gonads by reverse transcriptase-polymerase chain reaction and whole-mount in situ hybridization [25].
• In agreement with results observed in the transgenic mice, MIS decreased the rate of MDA-MB-468 tumor growth and the gain in mean tumor volume in severe combined immunodeficient mice compared with vehicle-treated controls (P=0.004) [3].
• Administration of MIS to mice was associated with a lower number of palpable mammary tumors compared with vehicle-treated mice (P=0.048), and the mean mammary tumor weight in the MIS-treated group was significantly lower compared with the control group (P=0.029) [3].
• Using rat organ genital ridge organ cultures, we found that inhibition of MMP2 activity prevented MIS-induced regression, whereas activation of MMP2 promoted ligand-independent Müllerian duct regression [26].
• The genetic manipulation of the mouse germline has lead to the generation of animal models for MIS function [27].

References