The mammalian hippo (Mst1 and Mst2) kinase plays a role in the lung development

Abstract

Respiratory distress syndrome (RDS), which is induced by insufficient production of surfactant, is the leading cause of mortality in preterm babies. While several transcription factors are known to be involved in surfactant protein expression, the molecular mechanisms and signaling pathways upstream of these transcription factors have remained elusive. Here, using Mst1/2 (mammalian sterile 20-like kinase 1/2) conditional knockout mice, we demonstrate that Mst1 and Mst2 kinases are critical for orchestration of transcription factors involved in surfactant protein homeostasis and prevention of RDS. Mice lacking Mst1/2 in the respiratory epithelium exhibited perinatal mortality with respiratory failure and their lungs contained fewer type I pneumocytes and more immature type II pneumocytes lacking microvilli, lamellar bodies, and surfactant protein expression, pointing to peripheral lung immaturity and RDS. In contrast to previous findings in the liver and intestine, loss of Mst1/2 kinases induced the defects in pneumocyte differentiation independently of YAP (Yes-associated protein) hyperactivity. We instead found that Mst1/2 kinases stabilized and phosphorylated the transcription factor Foxa2, which regulates pneumocyte maturation and surfactant protein expression. Taken together, our results suggest that Mst1 and Mst2 kinases play crucial roles in surfactant homeostasis and coordination of peripheral lung differentiation through regulation of Foxa2.