Differential role of FGF9 on epithelium and mesenchyme in mouse embryonic lung

Moral, Pierre-Marie del; Langhe, Stijn P. De; Sala, F.G.; Veltmaat, Jacqueline M.; Tefft, Denise; Wang, Kasper; Warburton, David; Bellusci, Savério

doi:10.1016/j.ydbio.2006.01.020

Cited by 108 publications

(170 citation statements)

References 38 publications

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“…Treatment of lung explants with FGF9 causes increased mesenchymal growth and luminal dilation of epithelial tubules (del Moral et al, 2006;Yin et al, 2011). We investigated the response of Mek1 flox/flox ;Mek2 −/− ;Dermo1 +/Cre explants to FGF9.…”

Section: Dermo1mentioning

confidence: 99%

Crucial requirement of ERK/MAPK signaling in respiratory tract development

et al. 2014

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There was an error published in Development 141, 3197-3211.In the key for Fig. 3C, the grey bars were labelled with the incorrect genotype name. The correct genotype is Mek1 +/flox ;Mek2+/cre . This error does not affect the conclusions of the paper.The authors apologise to readers for this mistake. In vitro, the loss of Mek function in lung mesenchyme did not interfere with lung growth and branching, suggesting that both the reduced intrathoracic space due to the dysmorphic rib cage and the omphalocele impaired lung development in vivo. Conversely, Mek mutation in the respiratory epithelium caused lung agenesis, a phenotype resulting from the direct impact of the ERK/MAPK pathway on cell proliferation and survival. No tracheal epithelial cell differentiation occurred and no SOX2-positive progenitor cells were detected in mutants, implying a role for the ERK/MAPK pathway in trachea progenitor cell maintenance and differentiation. Moreover, these anomalies were phenocopied when the Erk1 and Erk2 genes were mutated in airway epithelium. Thus, the ERK/MAPK pathway is required for the integration of mesenchymal and epithelial signals essential for the development of the entire respiratory tract.

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Section: Dermo1mentioning

confidence: 99%

Crucial requirement of ERK/MAPK signaling in respiratory tract development

et al. 2014

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“…Furthermore, while Elf5 expression was increased in the lung epithelium, we observed no effects of FGF2 and FGF9 on the tracheal epithelium. It has been previously reported that FGF9 null embryos have decreased FGF10 expression in the lung mesenchyme (Colvin et al, 2001), and FGF7 and FGF10 expression increased in cultured embryonic lungs with the addition of FGF9 (del Moral et al, 2006;White et al, 2006). Exogenous FGF9 has also been shown to increase expression of genes that are known to be FGF7 and FGF10 responsive (White et al, 2006).…”

Section: Elf5 Is An Fgf-sensitive Epithelium-specific Gene In the Lungmentioning

confidence: 89%

Elf5 is an epithelium‐specific, fibroblast growth factor–sensitive transcription factor in the embryonic lung

Metzger¹,

Xu²,

Shannon³

2007

Developmental Dynamics

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Fibroblast growth factor (FGF) signaling has been shown to be essential for many aspects of normal lung development. To determine epithelial targets of FGF signaling, we cultured embryonic day (E) 11.5 mouse lungs for 24 hr in the presence or absence of the FGF receptor antagonist SU5402, which inhibited branching morphogenesis. Affymetrix gene chip analysis of treated and control epithelia identified several genes regulated by FGF signaling, including Elf5, a member of the Epithelial-specific Ets family of transcription factors. SU5402 reduced Elf5 expression in mesenchyme-free cultures of E12.5 epithelium, demonstrating that the inhibition was direct. In situ hybridization revealed that Elf5 had a dynamic pattern of expression during lung development. We found that expression of Elf5 was induced by FGF7 and FGF10, ligands that primarily bind FGFR2b. To further define the pathways by which FGFs activate Elf5 expression, we cultured E11.5 lung tips in the presence of compounds to inhibit FGF receptors (SU5402), PI3-Kinase/Akt-mediated signaling (LY294002), and MAP Kinase/Erk-mediated signaling (U0126). We found that SU5402 and LY294002 significantly reduced Elf5 expression, whereas U0126 had no effect. LY294002 also reduced Elf5 expression in cultures of purified epithelium. Finally, pAkt was coexpressed with Elf5 in the proximal epithelial airways of E17.5 lungs. These results demonstrate that Elf5 is an FGF-sensitive transcription factor in the lung with a dynamic pattern of expression and that FGF regulation of Elf5 by means of FGFR2b occurs through the PI3-Kinase/Akt pathway.

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“…Addition of FGF9, another FGF important for lung development, to lung explant cultures also causes cyst-like structures (del Moral et al, 2006). Fgf9 overexpression in lung epithelium induces epithelial branching arrest and luminal dilation in combination with decreased and increased Shh and Fgf10 expression, respectively (White et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Epithelial inactivation of Yy1 abrogates lung branching morphogenesis

et al. 2015

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Yin Yang 1 (YY1) is a multifunctional zinc-finger-containing transcription factor that plays crucial roles in numerous biological processes by selectively activating or repressing transcription, depending upon promoter contextual differences and specific protein interactions. In mice, Yy1 null mutants die early in gestation whereas Yy1 hypomorphs die at birth from lung defects. We studied how the epithelial-specific inactivation of Yy1 impacts on lung development. The Yy1 mutation in lung epithelium resulted in neonatal death due to respiratory failure. It impaired tracheal cartilage formation, altered cell differentiation, abrogated lung branching and caused airway dilation similar to that seen in human congenital cystic lung diseases. The cystic lung phenotype in Yy1 mutants can be partly explained by the reduced expression of Shh, a transcriptional target of YY1, in lung endoderm, and the subsequent derepression of mesenchymal Fgf10 expression. Accordingly, SHH supplementation partially rescued the lung phenotype in vitro. Analysis of human lung tissues revealed decreased YY1 expression in children with pleuropulmonary blastoma (PPB), a rare pediatric lung tumor arising during fetal development and associated with DICER1 mutations. No evidence for a potential genetic interplay between murine Dicer and Yy1 genes during lung morphogenesis was observed. However, the cystic lung phenotype resulting from the epithelial inactivation of Dicer function mimics the Yy1 lung malformations with similar changes in Shh and Fgf10 expression. Together, our data demonstrate the crucial requirement for YY1 in lung morphogenesis and identify Yy1 mutant mice as a potential model for studying the genetic basis of PPB.

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Differential role of FGF9 on epithelium and mesenchyme in mouse embryonic lung

Cited by 108 publications

References 38 publications

Crucial requirement of ERK/MAPK signaling in respiratory tract development

Crucial requirement of ERK/MAPK signaling in respiratory tract development

Elf5 is an epithelium‐specific, fibroblast growth factor–sensitive transcription factor in the embryonic lung

Epithelial inactivation of Yy1 abrogates lung branching morphogenesis

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