Paracrine-mediated apoptosis in reproductive tract development

In mammalian development, the signaling pathways that couple extracellular death signals with the apoptotic machinery are still poorly understood. We chose to examine Mullerian duct regression in the developing reproductive t ract as a possible model of apoptosis during morphogenesis. The TGF beta-li ke hormone, Mullerian inhibiting substance (MIS), initiates regression of t he Mullerian duct or female reproductive tract anlagen; this event is essen tial for proper male sexual differentiation and occurs between embryonic da ys (E) 14 and 17 in the rat. Here, we show that apoptosis occurs during Mul lerian duct regression in male embryos beginning at E15. Female Mullerian d ucts exposed to MIS also exhibited prominent apoptosis within 13 h, which w as blocked by a caspase inhibitor. In both males and females the MIS type-I I receptor is expressed exclusively in the mesenchymal cell layer surroundi ng the duct, whereas apoptotic cells localize to the epithelium. In additio n, tissue recombination experiments provide evidence that MIS does not act directly on the epithelium to induce apoptosis Based on these data, we sugg est that MIS triggers cell death by altering mesenchymal-epithelial interac tions, (C) 1999 Academic Press.