Tif1γ is essential for the terminal differentiation of mammary alveolar epithelial cells and for lactation through SMAD4 inhibition.

Transforming growth factor beta (TGF beta) is widely recognised as an important factor that regulates many steps of normal mammary gland (MG) development, including branching morphogenesis, functional differentiation and involution. Tif1 gamma has previously been reported to temporally and spatially control TGF beta signalling during early vertebrate development by exerting negative effects over SMAD4 availability. To evaluate the contribution of Tif1 gamma to MG development, we developed a Cre/LoxP system to specifically invalidate the Tif1g gene in mammary epithelial cells in vivo. Tif1g-null mammary gland development appeared to be normal and no defects were observed during the lifespan of virgin mice. However, a lactation defect was observed in mammary glands of Tif1g-null mice. We demonstrate that Tif1 gamma is essential for the terminal differentiation of alveolar epithelial cells at the end of pregnancy and to ensure lactation. Tif1 gamma appears to play a crucial role in the crosstalk between TGF beta and prolactin pathways by negatively regulating both PRL receptor expression and STAT5 phosphorylation, thereby impairing the subsequent transactivation of PRL target genes. Using HC11 cells as a model, we demonstrate that the effects of Tif1g knockdown on lactation depend on both SMAD4 and TGF beta. Interestingly, we found that the Tif1 gamma expression pattern in mammary epithelial cells is almost symmetrically opposite to that described for TGF beta. We propose that Tif1 gamma contributes to the repression of TGF beta activity during late pregnancy and prevents lactation by inhibiting SMAD4.