title: Terminal end bud maintenance in mammary gland is dependent upon FGFR2b signaling.
abstract: We previously demonstrated that Fibroblast Growth Factor 10 (FGF10) and its receptor FGFR2b play a key role in controlling the very early stages of mammary gland development during embryogenesis [Mailleux, A.A., Spencer-Dene, B., Dillon, C., Ndiaye, D., Savona-Baron, C., Itoh, N., Kato, S., Dickson, C., Thiery, J.P., and Bellusci, S. (2002). Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo. Development 129, 53-60. Veltmaat, J. M., Relaix, F., Le, L.T., Kratochwil, K., Sala, F.G., van Veelen, W., Rice, R., Spencer-Dene, B., Mailleux, A.A., Rice, D.P., Thiery, J.P., and Bellusci, S. (2006). Gli3-mediated somitic Fgf10 expression gradients are required for the induction and patterning of mammary epithelium along the embryonic axes. Development 133, 2325-35.]. However, the role of FGFR2b signaling in postnatal mammary gland development is still elusive. We show that FGF10 is expressed at high level throughout the adipose tissue in the mammary gland of young virgin female mice whereas its main receptor FGFR2 is found mostly in the epithelium. Using a rtTA transactivator/tetracycline promoter approach allowing inducible and reversible attenuation of the FGFR2b signaling throughout the adult mouse, we are now reporting that FGFR2b signaling is also critical during postnatal mammary gland development. Ubiquitous attenuation of FGFR2b signaling in the postnatal mouse for 6 weeks starting immediately after birth is not lethal and leads to minor defects in the animal. Upon dissection of the mammary glands, a 40% reduction in size compared to the WT control is observed. Further examination shows a rudimentary mammary epithelial tree with completely absent terminal end buds (TEBs), compared to a well-branched structure observed in wild type. Transplantation of mammary gland explants into cleared fat pad of wild type mouse recipients indicates that the observed abnormal branching results from defective FGFR2b signaling in the epithelium. We also demonstrate that this rudimentary tree reforms TEBs and resumes branching upon removal of doxycycline suggesting that the regenerative capacities of the mammary epithelial progenitor cells were still functional despite long-term inactivation of the FGFR2b pathway. At the cellular level, upon FGFR2b attenuation, we show an increase in apoptosis associated with a decrease in the proliferation of the mammary luminal epithelium. We conclude that during puberty, there is a differential requirement for FGFR2b signaling in ductal vs. TEBs epithelium. FGFR2b signaling is crucial for the survival and proliferation of the mammary luminal epithelial cells, but does not affect the regenerative potential of the mammary epithelial progenitor cells.
authors.affiliation: Developmental Biology Program, Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Parsa
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Ramasamy
authors.forename: Stijn
authors.initials: S
authors.lastname: De Langhe
authors.forename: Varsha V
authors.initials: VV
authors.lastname: Gupte
authors.forename: Jody J
authors.initials: JJ
authors.lastname: Haigh
authors.forename: Daniel
authors.initials: D
authors.lastname: Medina
authors.forename: Savério
authors.initials: S
authors.lastname: Bellusci
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology
chemical_list: C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2