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.

A Dynamic WNT/β-CATENIN Signaling Environment Leads to WNT-Independent and WNT-Dependent Proliferation of Embryonic Intestinal Progenitor Cells

“…Interestingly, studies in the embryonic lung have shown that Sox9 is not regulated by WNT/β-CATENIN; rather, it is likely downstream of FGF signaling (Chang et al., 2013, Rockich et al., 2013). Moreover, Fgf10 has been demonstrated to play a role in suppressing cytodifferentiation in the developing intestine (Nyeng et al., 2011). Thus, it is interesting to speculate that fibroblast growth factor signaling may play a role regulating progenitor cell proliferation during the pseudostratified stage.…”

Sox2 and Fgf interact with Atoh1 to promote sensory competence throughout the zebrafish inner ear

“…A distinct alternative model is that Fgf8 and Sox2 promote sensory competence by inducing a state of increased pluripotency. Both factors can promote formation of stem cells or multi-potent progenitors associated with early stages of tissue development (Graham et al, 2003; Nyeng et al, 2011; Tucker et al, 2010; reviewed by Lanner and Rossant, 2010). Thus, elevating Fgf8 or Sox2 could reverse early stages of differentiation of non-sensory cell types, thereby making cells more susceptible to Atoh1 activity.…”

Formation of duodenal atresias in fibroblast growth factor receptor 2IIIb−/− mouse embryos occurs in the absence of an endodermal plug

“…In the absence of viable endoderm, the atretic precursor mesoderm involutes by a mechanism other than cell death. Recent work by Nyeng et al indicates that the loss of Fgf10 expression results in the premature differentiation of the progenitor niche in this region whereas over expression result in the expansion of this niche [12]. Together, these data suggest a more complex mechanism of duodenal atresia formation whereby a combination of endodermal cell death and terminal differentiation of progenitor cells results in formation of this defect.…”