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Formation and differentiation of multiple mesenchymal lineages during lung development is regulated by beta-catenin signaling.

De Langhe SP, Carraro G, Tefft D, Li C, Xu X, Chai Y, Minoo P, Hajihosseini MK, Drouin J, Kaartinen V, Bellusci S - PLoS ONE (2008)

Bottom Line: The amplification but not differentiation of Fgf10-expressing parabronchial smooth muscle progenitor cells is drastically reduced.In the angioblast-endothelial lineage, however, only differentiation into mature endothelial cells is impaired.Taken together these findings reveal a hierarchy of gene activity involving ss-catenin and PITX, as important regulators of mesenchymal cell proliferation and differentiation.

View Article: PubMed Central - PubMed

Affiliation: Developmental Biology Program, Department of Surgery, Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, California, USA.

ABSTRACT

Background: The role of ss-catenin signaling in mesodermal lineage formation and differentiation has been elusive.

Methodology: To define the role of ss-catenin signaling in these processes, we used a Dermo1(Twist2)(Cre/+) line to target a floxed beta-catenin allele, throughout the embryonic mesenchyme. Strikingly, the Dermo1(Cre/+); beta-catenin(f/-) conditional Knock Out embryos largely phenocopy Pitx1(-/-)/Pitx2(-/-) double knockout embryos, suggesting that ss-catenin signaling in the mesenchyme depends mostly on the PITX family of transcription factors. We have dissected this relationship further in the developing lungs and find that mesenchymal deletion of beta-catenin differentially affects two major mesenchymal lineages. The amplification but not differentiation of Fgf10-expressing parabronchial smooth muscle progenitor cells is drastically reduced. In the angioblast-endothelial lineage, however, only differentiation into mature endothelial cells is impaired.

Conclusion: Taken together these findings reveal a hierarchy of gene activity involving ss-catenin and PITX, as important regulators of mesenchymal cell proliferation and differentiation.

Show MeSH
Reduced Fgf10, Spry2, Spry4 and Pitx2 expression in CKO lungs.Gene expression in E13.5 lungs by WMISH and LacZ staining in WT and CKO lungs (n = 3 for each probe). (a–b) Fgf10 expression is reduced in the sub-mesothelial mesenchyme of CKO lungs. Inset: vibratome section through the distal left lobes. (c–d) Spry2 expression is reduced in the epithelium of CKO lungs. (e–f) No difference in Shh or (g–h) Ptch expression levels in CKO lungs compared to WT lungs. Inset : vibratome section through the distal right lobes. (i–j) Spry4 expression is reduced in the distal mesenchyme of CKO lungs illustrating reduced mesenchymal FGF9 signaling. (k–l) β-gal staining of TOPGAL lungs shows similar levels of TOPGAL activity in WT and CKO lungs illustrating the specificity of the β-catenin deletion throughout the mesenchyme. (o–n) Pitx2 is completely ablated in CKO lungs at E13.5. (o–p) Pitx2 expression is still present in E11.5 CKO embryos even though the Pitx2−/− phenotype is already apparent indicating that interaction of PITX2 with β-catenin is necessary for β-catenin signaling.
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pone-0001516-g003: Reduced Fgf10, Spry2, Spry4 and Pitx2 expression in CKO lungs.Gene expression in E13.5 lungs by WMISH and LacZ staining in WT and CKO lungs (n = 3 for each probe). (a–b) Fgf10 expression is reduced in the sub-mesothelial mesenchyme of CKO lungs. Inset: vibratome section through the distal left lobes. (c–d) Spry2 expression is reduced in the epithelium of CKO lungs. (e–f) No difference in Shh or (g–h) Ptch expression levels in CKO lungs compared to WT lungs. Inset : vibratome section through the distal right lobes. (i–j) Spry4 expression is reduced in the distal mesenchyme of CKO lungs illustrating reduced mesenchymal FGF9 signaling. (k–l) β-gal staining of TOPGAL lungs shows similar levels of TOPGAL activity in WT and CKO lungs illustrating the specificity of the β-catenin deletion throughout the mesenchyme. (o–n) Pitx2 is completely ablated in CKO lungs at E13.5. (o–p) Pitx2 expression is still present in E11.5 CKO embryos even though the Pitx2−/− phenotype is already apparent indicating that interaction of PITX2 with β-catenin is necessary for β-catenin signaling.

Mentions: In the developing lungs, Fgf10 is expressed by the PSMC progenitors, which are sub-mesothelial in origin [26]. Localized expression of Fgf10 in the distal mesenchyme also drives the stereotypic branching observed during early lung development [27]. Except for a few patches in the right lobes, levels of Fgf10 were greatly reduced in E13.5 CKO lungs (Fig. 3a,b) and these patches likely reflect the mosaicism of ß-catenin inactivation. Vibratome sections showed that in the left lobes there is almost complete absence of Fgf10 expression (insets in Fig. 3a,b). Interestingly, we also found a marked reduction in Spry2 expression in the distal epithelium of CKO lungs (Fig. 3c,d). As a read out, Spry2 reduction is indicative of reduced epithelial FGF signaling and correlates with decreased epithelial branching [26].


Formation and differentiation of multiple mesenchymal lineages during lung development is regulated by beta-catenin signaling.

De Langhe SP, Carraro G, Tefft D, Li C, Xu X, Chai Y, Minoo P, Hajihosseini MK, Drouin J, Kaartinen V, Bellusci S - PLoS ONE (2008)

Reduced Fgf10, Spry2, Spry4 and Pitx2 expression in CKO lungs.Gene expression in E13.5 lungs by WMISH and LacZ staining in WT and CKO lungs (n = 3 for each probe). (a–b) Fgf10 expression is reduced in the sub-mesothelial mesenchyme of CKO lungs. Inset: vibratome section through the distal left lobes. (c–d) Spry2 expression is reduced in the epithelium of CKO lungs. (e–f) No difference in Shh or (g–h) Ptch expression levels in CKO lungs compared to WT lungs. Inset : vibratome section through the distal right lobes. (i–j) Spry4 expression is reduced in the distal mesenchyme of CKO lungs illustrating reduced mesenchymal FGF9 signaling. (k–l) β-gal staining of TOPGAL lungs shows similar levels of TOPGAL activity in WT and CKO lungs illustrating the specificity of the β-catenin deletion throughout the mesenchyme. (o–n) Pitx2 is completely ablated in CKO lungs at E13.5. (o–p) Pitx2 expression is still present in E11.5 CKO embryos even though the Pitx2−/− phenotype is already apparent indicating that interaction of PITX2 with β-catenin is necessary for β-catenin signaling.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211394&req=5

pone-0001516-g003: Reduced Fgf10, Spry2, Spry4 and Pitx2 expression in CKO lungs.Gene expression in E13.5 lungs by WMISH and LacZ staining in WT and CKO lungs (n = 3 for each probe). (a–b) Fgf10 expression is reduced in the sub-mesothelial mesenchyme of CKO lungs. Inset: vibratome section through the distal left lobes. (c–d) Spry2 expression is reduced in the epithelium of CKO lungs. (e–f) No difference in Shh or (g–h) Ptch expression levels in CKO lungs compared to WT lungs. Inset : vibratome section through the distal right lobes. (i–j) Spry4 expression is reduced in the distal mesenchyme of CKO lungs illustrating reduced mesenchymal FGF9 signaling. (k–l) β-gal staining of TOPGAL lungs shows similar levels of TOPGAL activity in WT and CKO lungs illustrating the specificity of the β-catenin deletion throughout the mesenchyme. (o–n) Pitx2 is completely ablated in CKO lungs at E13.5. (o–p) Pitx2 expression is still present in E11.5 CKO embryos even though the Pitx2−/− phenotype is already apparent indicating that interaction of PITX2 with β-catenin is necessary for β-catenin signaling.
Mentions: In the developing lungs, Fgf10 is expressed by the PSMC progenitors, which are sub-mesothelial in origin [26]. Localized expression of Fgf10 in the distal mesenchyme also drives the stereotypic branching observed during early lung development [27]. Except for a few patches in the right lobes, levels of Fgf10 were greatly reduced in E13.5 CKO lungs (Fig. 3a,b) and these patches likely reflect the mosaicism of ß-catenin inactivation. Vibratome sections showed that in the left lobes there is almost complete absence of Fgf10 expression (insets in Fig. 3a,b). Interestingly, we also found a marked reduction in Spry2 expression in the distal epithelium of CKO lungs (Fig. 3c,d). As a read out, Spry2 reduction is indicative of reduced epithelial FGF signaling and correlates with decreased epithelial branching [26].

Bottom Line: The amplification but not differentiation of Fgf10-expressing parabronchial smooth muscle progenitor cells is drastically reduced.In the angioblast-endothelial lineage, however, only differentiation into mature endothelial cells is impaired.Taken together these findings reveal a hierarchy of gene activity involving ss-catenin and PITX, as important regulators of mesenchymal cell proliferation and differentiation.

View Article: PubMed Central - PubMed

Affiliation: Developmental Biology Program, Department of Surgery, Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, California, USA.

ABSTRACT

Background: The role of ss-catenin signaling in mesodermal lineage formation and differentiation has been elusive.

Methodology: To define the role of ss-catenin signaling in these processes, we used a Dermo1(Twist2)(Cre/+) line to target a floxed beta-catenin allele, throughout the embryonic mesenchyme. Strikingly, the Dermo1(Cre/+); beta-catenin(f/-) conditional Knock Out embryos largely phenocopy Pitx1(-/-)/Pitx2(-/-) double knockout embryos, suggesting that ss-catenin signaling in the mesenchyme depends mostly on the PITX family of transcription factors. We have dissected this relationship further in the developing lungs and find that mesenchymal deletion of beta-catenin differentially affects two major mesenchymal lineages. The amplification but not differentiation of Fgf10-expressing parabronchial smooth muscle progenitor cells is drastically reduced. In the angioblast-endothelial lineage, however, only differentiation into mature endothelial cells is impaired.

Conclusion: Taken together these findings reveal a hierarchy of gene activity involving ss-catenin and PITX, as important regulators of mesenchymal cell proliferation and differentiation.

Show MeSH