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Altered lung morphogenesis, epithelial cell differentiation and mechanics in mice deficient in the Wnt/β-catenin antagonist Chibby.

Love D, Li FQ, Burke MC, Cyge B, Ohmitsu M, Cabello J, Larson JE, Brody SL, Cohen JC, Takemaru K - PLoS ONE (2010)

Bottom Line: Notably, Cby protein is prominently associated with the centrosome/basal body microtubule structures in embryonic lung epithelial progenitor cells, and later enriches as discrete foci at the base of motile cilia in airway ciliated cells.At birth, Cby(-/-) lungs are grossly normal but spontaneously develop alveolar airspace enlargement with reduced proliferation and abnormal differentiation of lung epithelial cells, resulting in altered pulmonary function.Collectively, our results demonstrate that Cby facilitates proper postnatal lung development and function.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacological Sciences, SUNY at Stony Brook, Stony Brook, New York, United States of America.

ABSTRACT
The canonical Wnt/β-catenin pathway plays crucial roles in various aspects of lung morphogenesis and regeneration/repair. Here, we examined the lung phenotype and function in mice lacking the Wnt/β-catenin antagonist Chibby (Cby). In support of its inhibitory role in canonical Wnt signaling, expression of β-catenin target genes is elevated in the Cby(-/-) lung. Notably, Cby protein is prominently associated with the centrosome/basal body microtubule structures in embryonic lung epithelial progenitor cells, and later enriches as discrete foci at the base of motile cilia in airway ciliated cells. At birth, Cby(-/-) lungs are grossly normal but spontaneously develop alveolar airspace enlargement with reduced proliferation and abnormal differentiation of lung epithelial cells, resulting in altered pulmonary function. Consistent with the Cby expression pattern, airway ciliated cells exhibit a marked paucity of motile cilia with apparent failure of basal body docking. Moreover, we demonstrate that Cby is a direct downstream target for the master ciliogenesis transcription factor Foxj1. Collectively, our results demonstrate that Cby facilitates proper postnatal lung development and function.

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Reduced cell proliferation in postnatal Cby−/− lungs.(A) Representative immunofluorescent images of BrdU incorporation in P11 lungs are shown. Nuclei were visualized with DAPI. Scale bar, 2 µm. (B) Quantification of BrdU-positive cells shows a dramatic reduction in cell proliferation in Cby−/− lungs at P11 (n = 3 per genotype). Values are means ± SE. Student's t-test; **P<0.001.
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pone-0013600-g005: Reduced cell proliferation in postnatal Cby−/− lungs.(A) Representative immunofluorescent images of BrdU incorporation in P11 lungs are shown. Nuclei were visualized with DAPI. Scale bar, 2 µm. (B) Quantification of BrdU-positive cells shows a dramatic reduction in cell proliferation in Cby−/− lungs at P11 (n = 3 per genotype). Values are means ± SE. Student's t-test; **P<0.001.

Mentions: To gain insights into the hypoplastic lung phenotype of Cby−/− mice, we assessed cell proliferation and apoptosis in the postnatal lung at P11 when alveolarization is actively taking place. BrdU incorporation assays revealed a dramatically reduced number of proliferating cells in Cby−/− lungs (Figure 5). No significant difference in apoptosis was detected by immunostaining for activated caspase-3 (data not shown). It has been demonstrated that α-smooth muscle actin-positive myofibroblasts are located at the tips of newly forming, immature alveolar septa, and play important roles in septal formation [28]. However, immunofluorescent staining for α-smooth muscle actin showed a normal staining pattern in Cby−/− lungs at P11 (data not shown). These results suggest that the lung phenotype of Cby−/− mice is attributable, at least in part, to reduced proliferation rather than increased apoptosis or alveolar septation defects.


Altered lung morphogenesis, epithelial cell differentiation and mechanics in mice deficient in the Wnt/β-catenin antagonist Chibby.

Love D, Li FQ, Burke MC, Cyge B, Ohmitsu M, Cabello J, Larson JE, Brody SL, Cohen JC, Takemaru K - PLoS ONE (2010)

Reduced cell proliferation in postnatal Cby−/− lungs.(A) Representative immunofluorescent images of BrdU incorporation in P11 lungs are shown. Nuclei were visualized with DAPI. Scale bar, 2 µm. (B) Quantification of BrdU-positive cells shows a dramatic reduction in cell proliferation in Cby−/− lungs at P11 (n = 3 per genotype). Values are means ± SE. Student's t-test; **P<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2963606&req=5

pone-0013600-g005: Reduced cell proliferation in postnatal Cby−/− lungs.(A) Representative immunofluorescent images of BrdU incorporation in P11 lungs are shown. Nuclei were visualized with DAPI. Scale bar, 2 µm. (B) Quantification of BrdU-positive cells shows a dramatic reduction in cell proliferation in Cby−/− lungs at P11 (n = 3 per genotype). Values are means ± SE. Student's t-test; **P<0.001.
Mentions: To gain insights into the hypoplastic lung phenotype of Cby−/− mice, we assessed cell proliferation and apoptosis in the postnatal lung at P11 when alveolarization is actively taking place. BrdU incorporation assays revealed a dramatically reduced number of proliferating cells in Cby−/− lungs (Figure 5). No significant difference in apoptosis was detected by immunostaining for activated caspase-3 (data not shown). It has been demonstrated that α-smooth muscle actin-positive myofibroblasts are located at the tips of newly forming, immature alveolar septa, and play important roles in septal formation [28]. However, immunofluorescent staining for α-smooth muscle actin showed a normal staining pattern in Cby−/− lungs at P11 (data not shown). These results suggest that the lung phenotype of Cby−/− mice is attributable, at least in part, to reduced proliferation rather than increased apoptosis or alveolar septation defects.

Bottom Line: Notably, Cby protein is prominently associated with the centrosome/basal body microtubule structures in embryonic lung epithelial progenitor cells, and later enriches as discrete foci at the base of motile cilia in airway ciliated cells.At birth, Cby(-/-) lungs are grossly normal but spontaneously develop alveolar airspace enlargement with reduced proliferation and abnormal differentiation of lung epithelial cells, resulting in altered pulmonary function.Collectively, our results demonstrate that Cby facilitates proper postnatal lung development and function.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacological Sciences, SUNY at Stony Brook, Stony Brook, New York, United States of America.

ABSTRACT
The canonical Wnt/β-catenin pathway plays crucial roles in various aspects of lung morphogenesis and regeneration/repair. Here, we examined the lung phenotype and function in mice lacking the Wnt/β-catenin antagonist Chibby (Cby). In support of its inhibitory role in canonical Wnt signaling, expression of β-catenin target genes is elevated in the Cby(-/-) lung. Notably, Cby protein is prominently associated with the centrosome/basal body microtubule structures in embryonic lung epithelial progenitor cells, and later enriches as discrete foci at the base of motile cilia in airway ciliated cells. At birth, Cby(-/-) lungs are grossly normal but spontaneously develop alveolar airspace enlargement with reduced proliferation and abnormal differentiation of lung epithelial cells, resulting in altered pulmonary function. Consistent with the Cby expression pattern, airway ciliated cells exhibit a marked paucity of motile cilia with apparent failure of basal body docking. Moreover, we demonstrate that Cby is a direct downstream target for the master ciliogenesis transcription factor Foxj1. Collectively, our results demonstrate that Cby facilitates proper postnatal lung development and function.

Show MeSH
Related in: MedlinePlus