The role of Pten in the cell-fate determination of epithelial cells in lung development

Introduction: PTEN is a tumor suppressor that negatively regulates the PI3K/Akt pathway. We previously reported that the prenatal, lung epithelium-specific deletion of Pten gene in mice (SOPten^Δ/Δ) resulted in impaired alveolization and alveolar epithelial cell (AEC) differentiation. However, the mechanisms of PTEN in the regulation of lung development and epithelial cell differentiation are unclear. Aims: To determine the roles of epithelial PTEN in the cell-fate decision of epithelial cells in lung development. Methods: We conducted histological and biochemical analyses of SOPten^Δ/Δ. Further mechanistic analyses were performed in vitro and in vivo. Results: The lung epithelial cells isolated from SOPten^Δ/Δ mice showed increased Calca, Scgb1a1, Muc5AC, Aqp5, Podoplanin and Sox2 mRNA expressions and decreased Sftpa mRNA expression at E18.5. Ultrastructure analysis showed hyperplasia of club cells and goblet cells. The septa of SOPten^Δ/Δ mice comprised type 1 AECs and numerous cuboidal cells with glycogen vacuoles but no lamellar bodies (i.e., bipotent progenitors); type 2 AECs were absent. SOPten^Δ/Δshowed increased CGRP- and podoplanin-positive cells but decreased SP-C-positive cells. Epithelial cells of SOPten^Δ/Δ lungs exhibited increased Mash1, Hes1 and Notch expressions. The induction of dominant-negative Pten gene in lung epithelial cells led to augmented Notch signaling and Sox2 expression. Conclusions: Our results demonstrate that epithelial PTEN has a vital role in controlling cell-fate choices during lung development by regulating Notch signaling, thereby providing the proper balance of functional epithelial lineages.