The restricted expression of the MIS type II receptor to the Müllerian mesenchyme and not the epithelium implies that involution of the Müllerian duct is a consequence of an indirect or paracrine signal emanating from the Müllerian mesenchyme

Apoptosis or programmed cell death is a major mechanism underlying morphogenetic events that sculpt the developing embryo. Prominent examples of cell death during vertebrate development include refinement of the immune system, specification of neuronal projections, formation of digits, and tail resorption during amphibian metamorphosis (see Jacobson et al., 1997). Müllerian duct regression is another example of a vertebrate developmental program involving cell death that results in the elimination of the primitive female reproductive tract in males. As such, this apoptotic event is an essential aspect of normal male sexual differentiation. The extracellular factor responsible for initiating the Müllerian duct regression program is the TGFβ-like hormone, Müllerian inhibiting substance (MIS or AMH) (see Nef and Parada, 2000; Roberts et al., 1999b). Members of the TGFβ gene family signal by the assembly of two related serine/threonine kinase receptors, referred to as type I or type II receptors, and downstream cytoplasmic Smad effector proteins (reviewed by Itoh et al., 2000). The MIS type II receptor (MISIIR) is expressed exclusively in the mesenchyme surrounding the Müllerian duct (Allard et al., 2000; Baarends et al., 1994; Roberts et al., 1999a), and at least for Müllerian duct regression, MIS employs a BMP-like signaling pathway and is able to signal through the type I receptor, ALK2 (Clarke et al., 2001; Gouedard et al., 2000; Visser et al., 2001). The specificity of the MIS signaling cascade is established by the restricted expression patterns of both the MIS ligand and the MIS type II receptor. Under normal circumstances, the mammalian embryonic ovary does not express MIS during sexual differentiation; consequently, the Müllerian duct fails to regress in females, and develops into the fallopian tubes, uterus and upper vagina. Conversely, the corresponding male reproductive tract, the Wolffian duct, is maintained in the male embryo because of testicular testosterone production, and becomes the epididymis, vas deferens and seminal vesicle (Nef and Parada, 2000). Addition of bioactive MIS to female genital ridges in culture results in Müllerian duct regression, suggesting that following MIS stimulation, females possess the full program to undergo duct regression in the urogenital ridge; thereby providing a unique opportunity to explore this morphogenetic process at an experimental level. The restricted expression of the MIS type II receptor to the Müllerian mesenchyme and not the epithelium implies that involution of the Müllerian duct is a consequence of an indirect or paracrine signal emanating from the Müllerian mesenchyme (Roberts et al., 1999a). This proposal predicts that MIS 1487 Development 129, 1487-1496 (2002) Printed in Great Britain © The Company of Biologists Limited 2002 DEV3565