Lung development requires an active ERK/MAPK pathway in the lung mesenchyme

Background: Reciprocal epithelial‐mesenchymal communications are critical throughout lung development, dictating branching morphogenesis and cell specification. Numerous signaling molecules are involved in these interactions, but the way epithelial‐mesenchymal crosstalk is coordinated remains unclear. The ERK/MAPK pathway transduces several important signals in lung formation. Epithelial inactivation of both Mek genes, encoding ERK/MAPK kinases, causes lung agenesis and death. Conversely, Mek mutation in mesenchyme results in lung hypoplasia, trachea cartilage malformations, kyphosis, omphalocele, and death. Considering the negative impact of kyphosis and omphalocele on intrathoracic space and, consequently, on lung growth, the exact role of ERK/MAPK pathway in lung mesenchyme remains unresolved. Results: To address the role of the ERK/MAPK pathway in lung mesenchyme in absence of kyphosis and omphalocele, we used the Tbx4Cre deleter mouse line, which acts specifically in lung mesenchyme. These Mek mutants did not develop kyphosis and omphalocele but they presented lung hypoplasia, tracheal defects, and neonatal death. Tracheal cartilage anomalies suggested a role for the ERK/MAPK pathway in the control of chondrocyte hypertrophy. Moreover, expression data indicated potential interactions between the ERK/MAPK and canonical Wnt pathways during lung formation. Conclusions: Lung development necessitates a functional ERK/MAPK pathway in the lung mesenchymal layer in order to coordinate efficient epithelial‐mesenchymal interactions. Developmental Dynamics 246:72–82, 2017. © 2016 Wiley Periodicals, Inc. Key findings ERK/MAPK pathway has a cell‐autonomous function in lung mesenchyme for correct lung growth and newborn survival. Reduced mesenchymal cell proliferation, increased apoptosis and decreased branching contribute to pulmonary hypoplasia in absence of Mek function in lung mesenchyme. A functional ERK/MAPK pathway in lung mesenchyme is not necessary for lung cell differentiation. ERK/MAPK pathway plays a potential role in the control of tracheal chondrocyte hypertrophy.