title: Tif1γ is essential for the terminal differentiation of mammary alveolar epithelial cells and for lactation through SMAD4 inhibition.
abstract: Transforming growth factor β (TGFβ) is widely recognised as an important factor that regulates many steps of normal mammary gland (MG) development, including branching morphogenesis, functional differentiation and involution. Tif1γ has previously been reported to temporally and spatially control TGFβ signalling during early vertebrate development by exerting negative effects over SMAD4 availability. To evaluate the contribution of Tif1 γ 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 γ is essential for the terminal differentiation of alveolar epithelial cells at the end of pregnancy and to ensure lactation. Tif1 γ appears to play a crucial role in the crosstalk between TGFβ 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 TGFβ. Interestingly, we found that the Tif1γ expression pattern in mammary epithelial cells is almost symmetrically opposite to that described for TGFβ. We propose that Tif1γ contributes to the repression of TGFβ activity during late pregnancy and prevents lactation by inhibiting SMAD4.
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm UMR-S1052, CNRS UMR5286, Centre Léon Bérard, Lyon, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Hesling
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lopez
authors.forename: Laurent
authors.initials: L
authors.lastname: Fattet
authors.forename: Philippe
authors.initials: P
authors.lastname: Gonzalo
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.forename: Daphné
authors.initials: D
authors.lastname: Blanchard
authors.forename: Régine
authors.initials: R
authors.lastname: Losson
authors.forename: Vincent
authors.initials: V
authors.lastname: Goffin
authors.forename: Natascha
authors.initials: N
authors.lastname: Pigat
authors.forename: Alain
authors.initials: A
authors.lastname: Puisieux
authors.forename: Ivan
authors.initials: I
authors.lastname: Mikaelian
authors.forename: Germain
authors.initials: G
authors.lastname: Gillet
authors.forename: Ruth
authors.initials: R
authors.lastname: Rimokh
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D004847:Epithelial Cells / Q000166:cytology* / Q000502:physiology; D005260:Female; D007774:Lactation / Q000235:genetics*; D008297:Male; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011247:Pregnancy; D015398:Signal Transduction / Q000235:genetics; D051901:Smad4 Protein / Q000037:antagonists & inhibitors* / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D014157:Transcription Factors; C491420:Trim33 protein, mouse