Mullerian inhibiting substance regulates its receptor/SMAD signaling and causes mesenchymal transition of the coelomic epithelial cells early in Mullerian duct regression
ABSTRACT Examination of Müllerian inhibiting substance (MIS) signaling in the rat in vivo and in vitro revealed novel developmental stage- and tissue-specific events that contributed to a window of MIS responsiveness in Müllerian duct regression. The MIS type II receptor (MISRII)-expressing cells are initially present in the coelomic epithelium of both male and female urogenital ridges, and then migrate into the mesenchyme surrounding the male Müllerian duct under the influence of MIS. Expression of the genes encoding MIS type I receptors, Alk2 and Alk3, is also spatiotemporally controlled; Alk2 expression appears earlier and increases predominantly in the coelomic epithelium, whereas Alk3 expression appears later and is restricted to the mesenchyme, suggesting sequential roles in Müllerian duct regression. MIS induces expression of Alk2, Alk3 and Smad8, but downregulates Smad5 in the urogenital ridge. Alk2-specific small interfering RNA (siRNA) blocks both the transition of MISRII expression from the coelomic epithelium to the mesenchyme and Müllerian duct regression in organ culture. Müllerian duct regression can also be inhibited or accelerated by siRNA targeting Smad8 and Smad5, respectively. Thus, the early action of MIS is to initiate an epithelial-to-mesenchymal transition of MISRII-expressing cells and to specify the components of the receptor/SMAD signaling pathway by differentially regulating their expression.
- SourceAvailable from: Rodolfo Rey
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- "The development of the M€ ullerian ducts occurs in three phases (Orvis and Behringer, 2007). Initially, there is a placode-like thickening of the coelomic epithelium, characterized by the expression of LIM1 and anti-M€ ullerian hormone receptor type II (AMHR-II) (Zhan et al., 2006; Arango et al., 2008). In the second phase, these primordial M€ ullerian cells invaginate from the coelomic epithelium to reach the Wolffian duct, induced by WNT4 expression from the mesonephros or coelomic epithelium (Vainio et al., 1999; Kobayashi et al., 2004). "
ABSTRACT: The birth of a baby with malformations of the genitalia urges medical action. Even in cases where the condition is not life-threatening, the identification of the external genitalia as male or female is emotionally essential for the family, and genital malformations represent one of the most stressful situations around a newborn. The female or male configuration of the genitalia normally evolves during fetal life according to the genetic, gonadal, and hormonal sex. Disorders of sex development occur when male hormone (androgens and anti-Müllerian hormone) secretion or action is insufficient in the 46,XY fetus or when there is an androgen excess in the 46,XX fetus. However, sex hormone defects during fetal development cannot explain all congenital malformations of the reproductive tract. This review is focused on those congenital conditions in which gonadal function and sex hormone target organ sensitivity are normal and, therefore, not responsible for the genital malformation. Furthermore, because the reproductive and urinary systems share many common pathways in embryo-fetal development, conditions associating urogenital malformations are discussed. Birth Defects Research (Part C), 2014. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.Birth Defects Research Part C Embryo Today Reviews 12/2014; 102(4). DOI:10.1002/bdrc.21086
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- "Since cumulus cells continue to proliferate at later stages of folliculogenesis, but mural cells do not (Hirshfield, 1986), FOXL2 may be involved in shaping and establishment of the different granulosa phenotypes that comprise the follicle during development. The differentiation-promoting activity of MIS is demonstrated in the mammalian model by the epithelial–mesenchymal transition that occurs during Müllerian duct regression in sexually differentiating males (Zhan et al., 2006). In medaka, the expression of mis has been associated with somatic cells that surround the primordial germ cells (PGCs) of both sexes starting approximately four days before proliferative activity (Shiraishi et al., 2008). "
ABSTRACT: The products of dax1, foxl2a and mis have each been shown to have proliferative and/or differentiative activities during mammalian organogenesis. These factors also play a role in regulating the biosynthesis of estrogen, particularly by modulating the activity of aromatase cyp19a. We demonstrate the transcription and translation of these genes during salmon embryogenesis. We were able to track sex-specific differences in these processes through accurate determination of the sex of each embryo and larva examined from genotyped microsatellites. We detected sex- and stage-specific immunolabeling of the embryonic gut, kidney, gonads, neural cord and skeletal muscle by DAX-1, FOXL2A and MIS. These results indicate the potential of these factors to mediate proliferation and/or differentiation programs during development of these tissues. As well, immunolabeling of skeletal muscle by CYP19B1 throughout the study reveals probable neurogenic activity associated with peripheral radial glial cells and the growing embryonic musculature.Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 11/2013; 168(1). DOI:10.1016/j.cbpb.2013.11.004
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- "Some have argued that the WD simply acts as a guide for caudal MD growth (O'Rahilly, 1973), whereas others have proposed that the MD partially or completely splits off from the WD after they make intimate contact with each other (Grünwald, 1941). Recent cell fate tracing experiments in the chick and the mouse have settled the debate by demonstrating that both the epithelium and mesenchyme of the Müllerian duct arise from coelomic epithelium (Guioli et al., 2007; Orvis and Behringer, 2007), as previously suggested by the expression pattern of Amhr2 (Zhan et al., 2006). In the cell fate tracing studies, the long debated cellular contribution of the WD to the MD (Del Vecchio, 1982; Frutiger, 1969) was not detected. "
ABSTRACT: In mammals, the female reproductive tract (FRT) develops from a pair of paramesonephric or Müllerian ducts (MDs), which arise from coelomic epithelial cells of mesodermal origin. During development, the MDs undergo a dynamic morphogenetic transformation from simple tubes consisting of homogeneous epithelium and surrounding mesenchyme into several distinct organs namely the oviduct, uterus, cervix and vagina. Following the formation of anatomically distinctive organs, the uniform MD epithelium (MDE) differentiates into diverse epithelial cell types with unique morphology and functions in each organ. Classic tissue recombination studies, in which the epithelium and mesenchyme isolated from the newborn mouse FRT were recombined, have established that the organ specific epithelial cell fate of MDE is dictated by the underlying mesenchyme. The tissue recombination studies have also demonstrated that there is a narrow developmental window for the epithelial cell fate determination in MD-derived organs. Accordingly, the developmental plasticity of epithelial cells is mostly lost in mature FRT. If the signaling that controls epithelial differentiation is disrupted at the critical developmental stage, the cell fate of MD-derived epithelial tissues will be permanently altered and can result in epithelial lesions in adult life. A disruption of signaling that maintains epithelial cell fate can also cause epithelial lesions in the FRT. In this review, the pathogenesis of cervical/vaginal adenoses and uterine squamous metaplasia is discussed as examples of such incidences.Differentiation 05/2011; 82(3):117-26. DOI:10.1016/j.diff.2011.04.008