FGF ligands of the postnatal mammary stroma regulate distinct aspects of epithelial morphogenesis

Abstract

FGF signaling is essential for mammary gland development, yet the mechanisms by which different members of the FGF family control stem cell function and epithelial morphogenesis in this tissue are not well understood. Here, we have examined the requirement of Fgfr2 in mouse mammary gland morphogenesis using a postnatal organ regeneration model. We found that tissue regeneration from basal stem cells is a multistep event, including luminal differentiation and subsequent epithelial branching morphogenesis. Basal cells lacking Fgfr2 did not generate an epithelial network owing to a failure in luminal differentiation. Moreover, Fgfr2 null epithelium was unable to undergo ductal branch initiation and elongation due to a deficiency in directional migration. We identified FGF10 and FGF2 as stromal ligands that control distinct aspects of mammary ductal branching. FGF10 regulates branch initiation, which depends on directional epithelial migration. By contrast, FGF2 controls ductal elongation, requiring cell proliferation and epithelial expansion. Together, our data highlight a pleiotropic role of Fgfr2 in stem cell differentiation and branch initiation, and reveal that different FGF ligands regulate distinct aspects of epithelial behavior.

SPRY1 regulates mammary epithelial morphogenesis by modulating EGFR-dependent stromal paracrine signaling and ECM remodeling

“…By contrast, down-regulation of EGFR signaling in fibroblasts leads to stunted epithelial branching. Taken together with our findings of the significance of FGFR signaling within the epithelium (15,16,42), the results show that EGFR and FGFR signaling constitute a critical part of the molecular basis of stromal-epithelial interactions during postnatal development, and their modulation by Sprouty genes is essential for mammary gland formation and homeostasis.…”

“…In the presence of fibrospheres, mammary epithelium underwent rapid cyst formation and collective migration, suggesting that fibroblast influence is likely to be paracrine in nature. Interestingly, similar epithelial responses could be triggered by local delivery, as in the case of fibrospheres, of FGF ligands (42). The data thus point to FGFs as candidate mediators of the epithelial responses.…”

“…Accordingly, we hypothesized that, if FGFs are indeed responsible for the Spry1 loss-of-function phenotype, then FGF production would be higher in Spry1KO fibroblasts than in Spry1het fibroblasts. To test this hypothesis, we examined mRNA expression of several Fgfs that are expressed in the mammary gland stroma (42). As predicted, some of these Fgfs, including Fgf1, Fgf7, Fgf8, Fgf9, and Fgf10 were more highly expressed in Spry1KO fibroblasts than in Spry1het fibroblasts (Fig.…”

“…FGF ligands play distinct roles in epithelial morphogenesis of the mammary gland and, when delivered locally on heparin beads rather than uniformly in the medium, can trigger cyst formation and/or collective migration similar to fibrospheres (42). Thus, likely candidates by which fibrospheres influence the epithelium are FGF ligands, which are major epithelial branching signals produced in the mammary gland stroma.…”

“…By contrast, EGFR signaling down-regulation due to gain of Sprouty function in the stromal fibroblasts led to retardation of epithelial branching. Indeed, epithelial branching is severely retarded or absent in the mammary stroma lacking Egfr function (24) or in the mammary epithelium lacking Fgfr (15,16,42).…”