Mesodermal Pten inactivation leads to alveolar capillary dysplasia-like phenotype
Caterina Tiozzo, … , Saverio Bellusci, Parviz Minoo
Caterina Tiozzo, … , Saverio Bellusci, Parviz Minoo
Published October 1, 2012
Citation Information: J Clin Invest. 2012;122(11):3862-3872. https://doi.org/10.1172/JCI61334.
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Research Article Pulmonology

Mesodermal Pten inactivation leads to alveolar capillary dysplasia-like phenotype

Abstract

Alveolar capillary dysplasia (ACD) is a congenital, lethal disorder of the pulmonary vasculature. Phosphatase and tensin homologue deleted from chromosome 10 (Pten) encodes a lipid phosphatase controlling key cellular functions, including stem/progenitor cell proliferation and differentiation; however, the role of PTEN in mesodermal lung cell lineage formation remains unexamined. To determine the role of mesodermal PTEN in the ontogeny of various mesenchymal cell lineages during lung development, we specifically deleted Pten in early embryonic lung mesenchyme in mice. Pups lacking Pten died at birth, with evidence of failure in blood oxygenation. Analysis at the cellular level showed defects in angioblast differentiation to endothelial cells and an accompanying accumulation of the angioblast cell population that was associated with disorganized capillary beds. We also found decreased expression of Forkhead box protein F1 (Foxf1), a gene associated with the ACD human phenotype. Analysis of human samples for ACD revealed a significant decrease in PTEN and increased activated protein kinase B (AKT). These studies demonstrate that mesodermal PTEN has a key role in controlling the amplification of angioblasts as well as their differentiation into endothelial cells, thereby directing the establishment of a functional gas exchange interface. Additionally, these mice could serve as a murine model of ACD.

Authors

Caterina Tiozzo, Gianni Carraro, Denise Al Alam, Sheryl Baptista, Soula Danopoulos, Aimin Li, Maria Lavarreda-Pearce, Changgong Li, Stijn De Langhe, Belinda Chan, Zea Borok, Saverio Bellusci, Parviz Minoo

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Figure 6

Analysis of epithelial differentiation suggests increased FGF signaling.

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Analysis of epithelial differentiation suggests increased FGF signaling....
(A–H) IHC in E18.5 lungs showing increased SPC and FGFR2 in epithelium of mutant lungs. CC10 and T1α staining showed no differences. (I) qRT-PCR for Fgfr2b, Fgf9, Fgf7, Wnt2b, Spry2, Etv4, Etv5, Bmp4, Shh, Ptch1, and Gli1 showed increased FGF10/FGFR2b signaling in epithelium of the Pten cKO lungs compared with the WT. (J) Western blot for epithelial markers showed increased progenitor markers (SPC and TTF1) in the Ptenfl/fl;Dermo-Cre lungs. Data represent 5 lungs/group. *Statistically significant: Fgf9, P ≤ 0.05; Fgf7, P ≤ 0.05; Fgfr2b, P ≤ 0.01; Spry2, P ≤ 0.05; Etv5, P ≤ 0.05; Bmp4, P ≤ 0.01; Shh, P ≤ 0.05; Ptch1, P ≤ 0.05; Gli1, P ≤ 0.01. (K and N) IHC for TTF1 and E-CAD/ID2 in E18.5 control and mutant lungs. TTF1 and E-CAD/ID2 double-positive cells, markers of distal epithelial cells, were increased in the mutant lungs. Scale bars: 25 μm (lower magnification), 10 μm (higher magnification) (A, B, M, N); 50 μm (lower magnification), 30 μm (higher magnification) (C, D, K, L); 50 μm (lower magnification), 25 μm (higher magnification) (E–H).