Early formation of the Müllerian duct is regulated by sequential actions of BMP/Pax2- and FGF/Lim1 signaling

Abstract

The Müllerian duct (MD) and Wolffian duct (WD) are embryonic tubular tissues giving rise to female- and male reproductive tracts, respectively. In amniote embryos, both MD and WD emerge bisexually, but subsequently degenerate in the males and females, respectively. Here, by using MD-specific gene manipulations in chicken embryos, we identify the molecular and cellular mechanisms that link the early MD specification to tubular invagination. Early (pre-) specification of MD precursors in the coelomic epithelium requires BMP signaling and its downstream target Pax2 in a WD-independent process. Subsequently, the BMP/Pax2 axis induces Lim1 expression, a hallmark of MD specification, for which FGF/ERK- and WD-derived signals are also required. Finally, the sequential actions of the BMP/Pax2- and FGF/Lim1 axes culminate in the epithelial invagination to form a tubular structure driven by an apical constriction, where apical accumulation of phospho-myosin light chain is positively regulated by FGF/ERK signaling. Our study delineates mechanisms governing the early formation of MD, and also serves as a paradiagmatic example of how an epithelial cell sheet is transformed to a tubular structure, a process seen in a variety of developmental contexts.