A genetic mechanism for cecal atresia: the role of the Fgf10 signaling pathway

Fairbanks, Timothy; Kanard, Robert; Langhe, Stijn P. De; Sala, F.G.; Moral, Pierre Del; Warburton, David; Anderson, Kathryn D.; Bellusci, Savério; Burns, R. Cartland

doi:10.1016/j.jss.2003.12.017

Cited by 27 publications

(27 citation statements)

References 61 publications

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“…This phenotype is similar to that obtained by Abler et al who used a general mesenchymal driver line (Dermo1 Cre ) to perform conditional gene inactivation of Fgf10 [14]. Last but not least, our research group has previously demonstrated that the gut is a major site of Fgf10 expression and that hypomorphic Fgf10 embryos (Fgf10 LacZ/2 ) suffered from cecal atresia [4]. Our data agrees with this finding as Fgf10 iCre/flox ; Tomato flox/+ embryos suffered from a hypomorph-like phenotype at the level of the cecum upon partial loss of function of Fgf10 (Fig.…”

Section: Discussionsupporting

confidence: 87%

“…Therefore, the data obtained with the Fgf10 LacZ line should always be validated using the proper Cre inducible line. Nevertheless, this line has helped identify the progeny of Fgf10-positive cells in the heart, lung, gut, mammary glands, brain [4,5,7,8,9,10,11] and limbs [Hajihosseini and Bellusci, unpublished results]. Thus, the Fgf10 iCre knock-in line characterized in this paper represents a novel tool that bypasses the pitfalls associated with the Fgf10 LacZ transgenic line.…”

Section: Discussionmentioning

confidence: 99%

“…The LacZ cassette was mapped and found to be integrated within regulatory elements lying 114 kb upstream of the endogenous Fgf10 coding sequence [7]. LacZ expression pattern observed in these mice closely mimics Fgf10 expression in the heart, lung, gut, mammary glands and brain [4,5,7,8,9,10,11]. The Fgf10 LacZ mouse reports Fgf10 expression and also results in a Fgf10 hypomorph as demonstrated by the phenotype of Fgf10 LacZ/2 (one copy of Fgf10 null and one copy of Fgf10 LacZ ) embryos.…”

Section: Introductionmentioning

confidence: 90%

“…Loss of function of either Fgf10 or Fgfr2b by genetic deletion leads to total failure of lung and limb formation as well as cecal and colonic atresia [1,2,3,4,5]. In addition to its vital role during development, Fgf10 over-expression attenuates bleomycininduced pulmonary fibrosis in mice [6].…”

Section: Introductionmentioning

confidence: 99%

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Characterization of a novel Fibroblast growth factor 10 (Fgf10) knock-in mouse line to target mesenchymal progenitors during embryonic development

Agha¹,

Alam²,

Carraro³

et al. 2012

Pneumologie

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Fibroblast growth factor 10 (Fgf10) is a key regulator of diverse organogenetic programs during mouse development, particularly branching morphogenesis. Fgf10-null mice suffer from lung and limb agenesis as well as cecal and colonic atresia and are thus not viable. To date, the Mlcv1v-nLacZ-24 transgenic mouse strain (referred to as Fgf10 LacZ ), which carries a LacZ insertion 114 kb upstream of exon 1 of Fgf10 gene, has been the only strain to allow transient lineage tracing of Fgf10-positive cells. Here, we describe a novel Fgf10 Cre-ERT2 knock-in line (Fgf10 iCre ) in which a Cre-ERT2-IRES-YFP cassette has been introduced in frame with the ATG of exon 1 of Fgf10 gene. Our studies show that Cre-ERT2 insertion disrupts Fgf10 function. However, administration of tamoxifen to Fgf10 iCre ; Tomato flox double transgenic embryos or adult mice results in specific labeling of Fgf10-positive cells, which can be lineage-traced temporally and spatially. Moreover, we show that the Fgf10 iCre line can be used for conditional gene inactivation in an inducible fashion during early developmental stages. We also provide evidence that transcription factors located in the first intron of Fgf10 gene are critical for maintaining Fgf10 expression over time. Thus, the Fgf10 iCre line should serve as a powerful tool to explore the functions of Fgf10 in a controlled and stage-specific manner.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Characterization of a novel Fibroblast growth factor 10 (Fgf10) knock-in mouse line to target mesenchymal progenitors during embryonic development

Agha¹,

Alam²,

Carraro³

et al. 2012

Pneumologie

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“…a loss of cecal development). In contrast to Fgf9, Fgf10 is expressed at multiple, specific mesenchymal sites along the rostrocaudal axis, including the pyloric, ileo-colonic and ano-rectal junctions Fairbanks et al, 2004). FGF10 signals to an epithelial receptor, FGFR2b, and both Fgf10 and Fgfr2b mutant mice fail to develop a cecal epithelial bud .…”

Section: Research Articlementioning

confidence: 99%

Reciprocal epithelial-mesenchymal FGF signaling is required for cecal development

et al. 2006

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Fibroblast growth factor (FGF) signaling mediates reciprocal mesenchymal-epithelial cell interactions in the developing mouse lung and limb. In the gastrointestinal (GI) tract, FGF10 is expressed in the cecal mesenchyme and signals to an epithelial splice form of FGF receptor (FGFR) 2 to regulate epithelial budding. Here, we identify FGF9 as a reciprocal epithelial-mesenchymal signal required for cecal morphogenesis. Fgf9 null (Fgf9 -/-) mouse embryos have agenesis of the embryonic cecum, lacking both mesenchymal expansion and an epithelial bud. In the cecal region of Fgf9 -/-embryos, mesenchymal expression of Fgf10 and Bmp4 is notably absent, whereas the expression of epithelial markers, such as sonic hedgehog, is not affected. Using epithelial and whole explant cultures, we show that FGF9 signals to mesenchymal FGFRs and that FGF10 signals to epithelial FGFRs. Taken together, these data show that an epithelial FGF9 signal is necessary for the expansion of cecal mesenchyme and the expression of mesenchymal genes that are required for epithelial budding. Thus, these data add to our understanding of FGF-mediated reciprocal epithelialmesenchymal signaling.

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Lack of discreet colocalization of epithelial apoptosis to the atretic precursor in the colon of the Fibroblast growth factor receptor 2IIIb mouse and staining consistent with cellular movement suggest a revised model of atresia formation

Kowalkowski

Zaremba

Rogers

et al. 2020

Developmental Dynamics

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Background: Colonic atresias in the Fibroblast growth factor receptor 2IIIb (Fgfr2IIIb) mouse model have been attributed to increased epithelial apoptosis and decreased epithelial proliferation at embryonic day (E) 10.5. We therefore hypothesized that these processes would colocalize to the distal colon where atresias occur (atretic precursor) and would be excluded or minimized from the proximal colon and small intestine. Results: We observed a global increase in intestinal epithelial apoptosis in Fgfr2IIIb −/− intestines from E9.5 to E10.5 that did not colocalize to the atretic precursor. Additionally, epithelial proliferations rates in Fgfr2IIIb −/− intestines were statistically indistinguishable to that of controls at E10.5 and E11.5. At E11.5 distal colonic epithelial cells in mutants failed to assume the expected pseudostratified columnar architecture and the continuity of the adjacent basal lamina was disrupted. Individual E-cadherin-positive cells were observed in the colonic mesenchyme. Conclusions: Our observations suggest that alterations in proliferation and apoptosis alone are insufficient to account for intestinal atresias and that these defects may arise from both a failure of distal colonic epithelial cells to develop normally and local disruptions in basal lamina architecture.

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A genetic mechanism for cecal atresia: the role of the Fgf10 signaling pathway

Cited by 27 publications

References 61 publications

Characterization of a novel Fibroblast growth factor 10 (Fgf10) knock-in mouse line to target mesenchymal progenitors during embryonic development

Characterization of a novel Fibroblast growth factor 10 (Fgf10) knock-in mouse line to target mesenchymal progenitors during embryonic development

Reciprocal epithelial-mesenchymal FGF signaling is required for cecal development

Lack of discreet colocalization of epithelial apoptosis to the atretic precursor in the colon of the Fibroblast growth factor receptor 2IIIb mouse and staining consistent with cellular movement suggest a revised model of atresia formation

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