Interactions between FGF and Wnt signals and Tbx3 gene expression in mammary gland initiation in mouse embryos

Abstract

Interactions between Wnts, Fgfs and Tbx genes are involved in limb initiation and the same gene families have been implicated in mammary gland development. Here we explore how these genes act together in mammary gland initiation. We compared expression of Tbx3 , the gene associated with the human condition ulnar-mammary syndrome, expression of the gene encoding the dual-specificity MAPK phosphatase Pyst1 /MKP3, which is an early response to FGFR1 signalling (as judged by sensitivity to the SU5402 inhibitor), and expression of Lef1 , encoding a transcription factor mediating Wnt signalling and the earliest gene so far known to be expressed in mammary gland development. We found that Tbx3 is expressed earlier than Lef1 and that Pyst1 is also expressed early but only transiently. Patterns of expression of Tbx3 , Pyst1 and Lef1 in different glands suggest that the order of mammary gland initiation is 3, 4, 1, 2 and 5. Consistent with expression of Pyst1 in the mammary gland, we detected expression of Fgfr1b , Fgf8 and Fgf9 in both surface ectoderm and mammary bud epithelium, and Fgf4 and Fgf17 in mammary bud epithelium. Beads soaked in FGF-8 applied to the flank of mouse embryos, at a stage just prior to mammary bud initiation, induce expression of Pyst1 and Lef1 and maintain Tbx3 expression in flank tissue surrounding the bead. Grafting beads soaked in the FGFR1 inhibitor, SU5402, abolishes Tbx3 , Pyst1 and Lef1 expression, supporting the idea that FGFR1 signalling is required for early mammary gland initiation. We also showed that blocking Wnt signalling abolishes Tbx3 expression but not Pyst1 expression. These data, taken together with previous findings, suggest a model in which Tbx3 expression is induced and maintained in early gland initiation by both Wnt and Fgf signalling through FGFR1.

Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape

“…S1 A-C and Datasets S1 and S2). Up-regulated genes included the mammary epithelium markers Krt8, Bmp2, Fgf17, Gata3, Pthlh, and Tbx3 (30,(43)(44)(45)(46)(47), as well as the mammary mesenchyme-specific genes Tbx18, Esr1, and Meox2 (30), thus validating our experimental approach (Fig. 1B and Datasets S1 and S2).…”

Identification of loci affecting teat number by genome-wide association studies on three pig populations

“…This gene plays a critical role in guiding the expression of T-box gene family in embryonic stem cell differentiation [31]. T-box3 , a member of the T-box gene family, has been reported to influence the development of mammary gland placodes via interacting with Wnt family member 10 ( Wnt10 ), lymphoid enhancer binding factor 1 ( lef-1 ), and fibroblast growth factor 10 ( Fgf10 ) [32–34]. Moreover, T-box3 variants have been implicated in the Ulnar-Mammary Syndrome in humans, a genetic disease characterized by nipple and breast hypoplasia or aplasia [35,36].…”

The T-Box transcription factor 3 in development and cancer

“…It is well established that TBX3 regulates this signalling pathway during mammary gland development and it has also been suggested that TBX3 lies downstream of FGF (86). Fillmore et al demonstrated that oestrogen and FGF signalling upregulated the expression of TBX3 in breast cancer (63).…”