title: Fibroblast growth factor 10 represses premature cell differentiation during establishment of the intestinal progenitor niche.
abstract: Spatio-temporal regulation of the balance between cell renewal and cell differentiation is of vital importance for embryonic development and adult homeostasis. Fibroblast growth factor signaling relayed from the mesenchyme to the epithelium is necessary for progenitor maintenance during organogenesis of most endoderm-derived organs, but it is still ambiguous whether the signal is exclusively mitogenic. Furthermore, the downstream mechanisms are largely unknown. In order to elucidate these questions we performed a complementary analysis of fibroblast growth factor 10 (Fgf10), gain-of-function and loss-of-function in the embryonic mouse duodenum, where the progenitor niche is clearly defined and differentiation proceeds in a spatially organized manner. In agreement with a role in progenitor maintenance, FGF10 is expressed in the duodenal mesenchyme during early development while the cognate receptor FGFR2b is expressed in the epithelial progenitor niche. Fgf10 gain-of-function in the epithelium leads to spatial expansion of the progenitor niche and repression of cell differentiation, while loss-of-function results in premature cell differentiation and subsequent epithelial hypoplasia. We conclude that FGF10 mediated mesenchymal-to-epithelial signaling maintains the progenitor niche in the embryonic duodenum primarily by repressing cell differentiation, rather than through mitogenic signaling. Furthermore, we demonstrate that FGF10-signaling targets include ETS-family transcription factors, which have previously been shown to regulate epithelial maturation and tumor progression.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, 1775 N Ursula St. B140, 80045 Aurora, CO, USA. Pia.Nyeng@med.lu.se
authors.forename: Pia
authors.initials: P
authors.lastname: Nyeng
authors.forename: Maureen Ann
authors.initials: MA
authors.lastname: Bjerke
authors.forename: Gitte Anker
authors.initials: GA
authors.lastname: Norgaard
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Qu
authors.forename: Sune
authors.initials: S
authors.lastname: Kobberup
authors.forename: Jan
authors.initials: J
authors.lastname: Jensen
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology* / Q000196:embryology; D051379:Mice; D008822:Mice, Transgenic; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D015398:Signal Transduction
chemical_list: C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D051497:Receptor, Fibroblast Growth Factor, Type 2