Müllerian-inhibiting substance function during mammalian sexual development

Mullerian inhibiting substance (MIS) is the gonadal hormone that causes regression of the Mullerian ducts, the anlagen of the female internal reproductive structures, during male embryogenesis. MIS is a member of the large transforming growth factor-beta (TGF beta) multigene family of glycoproteins that are involved in the regulation of growth and differentiation. The proteins in this gene family are all produced as dimeric precursors and undergo posttranslational processing for activation, requiring cleavage and dissociation to release bioactive C-terminal fragments. Similarly, the 140 kilodalton (kDa) disulfide-linked homodimer of MIS is proteolytically cleaved to generate its active C-terminal fragments. The sexually dimorphic expression of MIS in Sertoli cells of the testis and granulosa cells of the ovary is critical for normal differentiation of the internal reproductive tract structures. A number of extra-Mullerian functions such as control of germ cell maturation and gonadal morphogenesis, induction of the abdominal phase of testicular descent, suppression of lung maturation, and growth inhibition of transformed cells have also been proposed for this growth-inhibitory hormone and will be discussed. This article will summarize the current understanding of the biology and multiple functions of MIS including its activation, regulation, and mechanism of action and discuss areas of interest in ongoing research.

/pdf/mullerian-inhibiting-substance-a-gonadal-hormone-with-2d0u0vr7ch.pdf

Mullerian Inhibiting Substance: A Gonadal Hormone with Multiple Functions

https://www.musc.edu/mbes-ljg/Courses/Biology%20of%20Reproduction/Paper%20pdfs/Kloinisch%20et%20al%2004.pdf

Molecular and genetic regulation of testis descent and external genitalia development.

Male sex differentiation is driven by 2 hormones, testosterone and anti-mullerian hormone (AMH), responsible for the regression of mullerian ducts in male fetuses Mutations inactivating AMH or its receptor AMHRII lead to the persistent mullerian duct syndrome (PMDS) in otherwise normally virilized 46,XY males Our objective was to review the clinical, anatomical, and molecular features of PMDS based upon a review of the literature and upon 157 personal cases Three clinical presentations exist: bilateral cryptorchidism, unilateral cryptorchidism with contralateral hernia, and transverse testicular ectopia Abnormalities of male excretory ducts are frequent Testicular malignant degeneration occurs in 33% of adults with the disorder, while cancer of mullerian derivatives is less frequent Fertility is rare but possible if at least one testis is scrotal and its excretory ducts are intact Eighty families with 64 different mutations of the AMH gene have been identified, mostly in exons 1, 2, and 5 AMHRII gene mutations representing 58 different alleles have been discovered in 75 families The most common mutation, a 27-bp deletion in the kinase domain, was found in 30 patients of mostly Northern European origin In 12% of cases, no mutation of AMH or AMHRII has been detected, suggesting a disruption of other pathways involved in mullerian regression

/pdf/the-persistent-mullerian-duct-syndrome-an-update-based-upon-56hz7ul94s.pdf

The Persistent Müllerian Duct Syndrome: An Update Based Upon a Personal Experience of 157 Cases.

Male patients with Peutz-Jeghers syndrome (PJS) have defective spermatogenesis and are at increased risk of developing Sertoli cell tumors. Mutations in the Liver Kinase B1 (LKB1/STK11) gene are associated with the pathogenesis of PJS and have been identified in non-PJS patients with sporadic testicular cancers. The mechanisms controlled by LKB1 signaling in Sertoli cell functions and testicular biology have not been described. We have conditionally deleted the Lkb1 gene (Lkb1(cko)) in somatic testicular cells to define the molecular mechanisms involved in the development of the testicular phenotype observed in PJS patients. Focal vacuolization in some of the seminiferous tubules was observed in 4-week-old mutant testes but germ cell development appeared to be normal. However, similar to PJS patients, we observed progressive germ cell loss and Sertoli cell only tubules in Lkb1(cko) testes from mice older than 10 weeks, accompanied by defects in Sertoli cell polarity and testicular junctional complexes and decreased activation of the MAP/microtubule affinity regulating and focal adhesion kinases. Suppression of AMP kinase and activation of mammalian target of rapamycin (mTOR) signaling were also observed in Lkb1(cko) testes. Loss of Tsc1 or Tsc2 copies the progressive Lkb1(cko) phenotype, suggesting that dysregulated activation of mTOR contributes to the pathogenesis of the Lkb1(cko) testicular phenotype. Pten(cko) mice had a normal testicular phenotype, which could be explained by the comparative lack of mTOR activation detected. These studies describe the importance of LKB1 signaling in testicular biology and the possible molecular mechanisms driving the pathogenesis of the testicular defects observed in PJS patients.

Altered LKB1/AMPK/TSC1/TSC2/mTOR signaling causes disruption of Sertoli cell polarity and spermatogenesis

Mullerian Inhibiting Substance (MIS) causes regression of the Mullerian ducts during a critical period in embryonic development in male mammals. In Persistent Mullerian Duct Syndrome (PMDS), an autosomal recessive trait in humans and dogs, the Mullerian ducts fail to regress in otherwise normal males. Previously we reported that PMDS-affected dogs produce bioactive testicular MIS postnatally. The purpose of the present study was to determine whether PMDS-affected canine embryos appropriately express MIS mRNA and protein during the critical period for Mullerian duct regression. Homozygous (PMDS-affected) and normal canine embryos were removed from timed pregnancies. Gonadal sex and the degree of Mullerian duct regression were determined from histologic sections. Positive immunohistochemical staining for MIS was found in testis sections of PMDS-affected and normal male embryos. A 1.8-kb MIS mRNA transcript was detected in testes of PMDS-affected males and normal male embryos and neonates. Furthermore, equal amounts of MIS mRNA transcript were detected in testes of PMDS-affected embryos and normal male littermates during the critical period for Mullerian duct regression. These data support a hypothesis of target organ resistance, such as an abnormality in the putative MIS receptor, as the etiology of the defect in this dog model.

/pdf/mullerian-inhibiting-substance-is-present-in-embryonic-tpsjx9n1fv.pdf

Mullerian Inhibiting Substance is present in embryonic testes of dogs with Persistent Mullerian Duct Syndrome

The embryonic period during which Mullerian duct regression and Mullerian Inhibiting Substance (MIS) secretion occur was determined in canine embryos removed from timed pregnancies (32, 36, 37, 39, 42, and 46 days gestation). Sex chromosomes of each embryo were identified in metaphase spreads prepared from fibroblast cultures. Testicular differentiation, defined by seminiferous tubule formation and the presence of Sertoli cells and Leydig cells, and the degree of Mullerian duct regression were determined by careful morphologic analysis of histologic sections of canine embryonic gonads (n = 20) and Mullerian ducts (n = 20). MIS was detected immunohistochemically in embryonic testes using avidin-biotin complex enhancement of a specific rabbit polyclonal anti-MIS antibody. Testicular differentiation was observed at 36 days gestation. The earliest evidence of Mullerian duct regression in male embryos was observed at 36 days gestation, and regression was completed by 46 days gestation. Positive staining for MIS was present in testes from 36 to 46 days (n = 9). Staining was absent in the undifferentiated testis (n = 1) at 32 days gestation and in ovaries at all ages tested (n = 10). Thus, MIS is normally present throughout the critical period for Mullerian duct regression in the embryonic male dog.

/pdf/the-critical-period-for-mullerian-duct-regression-in-the-dog-3urhtpscj4.pdf

The critical period for mullerian duct regression in the dog embryo.

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Mullerian Inhibiting Substance is present in embryonic testes of dogs with Persistent Mullerian Duct Syndrome

The critical period for mullerian duct regression in the dog embryo.