Mullerian inhibiting substance regulates its receptor/SMAD signaling and causes mesenchymal transition of the coelomic epithelial cells in Mullerian duct regression

Harvard University, Cambridge, Massachusetts, United States
Development (Impact Factor: 6.46). 07/2006; 133(12):2359-69. DOI: 10.1242/dev.02383
Source: PubMed


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.

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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). "
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    • "This pattern is also observed in mice (Fujino et al., 2009). Although PI3K signaling has been shown to prevent apoptosis and the epithelial to mesenchymal transitions that take place during MD regression, it is not clear if this reduction in p-AKT is a cause or effect of regression (Allard et al., 2000; Dyche, 1979; Fujino et al., 2009; Trelstad et al., 1982; Zhan et al., 2006). AMH signaling has been shown to inactivate the PI3K pathway by blocking autophosphorylation of the EGF receptor in the MD epithelium by inhibiting tyrosine kinase (Hurst et al., 2002; Hutson et al., 1984). "
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    • "We and others have also shown that expression of the MIS type I receptors, is also spatiotemporally controlled, and that the SMAD1, 5 and 8 subfamily of intracellular signal transducers are involved in MD regression (Gouedard et al., 2000; Clarke et al., 2001; Visser et al., 2001; Zhan et al., 2006; Orvis et al., 2008). with SMAD8 being predominantly expressed over SMAD1 and over SMAD5, which is poorly expressed during MD regression (Clarke et al., 2001; Zhan et al., 2006) One of the important unanswered questions in MD regression is how MISR2, which is expressed in the mesenchyme surrounding the MD but not in the MD epithelial cells at the time of regression (Baarends et al., 1994; di Clemente et al., 1994; Teixeira et al., 1996), induces apoptosis in the neighboring epithelial cells (Tsuji et al., 1992; Catlin et al., 1997; Allard et al., 2000). WNT/β-catenin signaling is known to be crucial for normal uterine development from the MDs in females (Kobayashi and Behringer 2003). "
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