Overexpression of a kinase-deficient transforming growth factor-beta type II receptor in mouse mammary stroma results in increased epithelial branching

Members of the transforming growth factor-beta (TGF-beta) superfamily signa l through heteromeric type I and type Il serine/threonine kinase receptors. Transgenic mice that overexpress a dominant-negative mutation of the TGF-b eta type II receptor (DNIIR) under the control of a metallothionein-derived promoter (MT-DNIIR) were used to determine the role of endogenous TGF-beta s in the developing mammary gland. The expression of the dominant-negative receptor was induced with zinc and was primarily localized to the stroma u nderlying the ductal epithelium in the mammary glands of virgin transgenic mice from two separate mouse lines. In MT-DNIIR virgin females treated with zinc, there was an increase in lateral branching of the ductal epithelium. We tested the hypothesis that expression of the dominant-negative receptor may alter expression of genes that are expressed in the stroma and regulat ed by TGF-beta s, potentially resulting in the increased lateral branching seen in the MT-DNIIR mammary glands. The expression of hepatocyte growth fa ctor mRNA was increased in mammary glands from transgenic animals relative to the wild-type controls, suggesting that this factor may play a role in T GF-beta-mediated regulation of lateral branching. Loss of responsiveness to TGF-beta s in the mammary stroma resulted in increased branching in mammar y epithelium, suggesting that TGF-beta s play an important role in the stro mal-epithelial interactions required for branching morphogenesis.