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

Abstract

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 / Δ showed 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.