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

Abstract

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 epithelialmesenchymal 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. V C 2016 Wiley Periodicals, Inc.

HOXA5 plays tissue-specific roles in the developing respiratory system

“…Specimens were processed for paraffin (4 µm) or frozen (5-10 µm) sections. Experiments were performed as described (Boucherat et al, 2017). Slides were counterstained with Nuclear Fast Red, Alcian Blue or Hematoxylin.…”

ERK1/2 Signaling Pathway Activated by EGF Promotes Proliferation, Transdifferentiation, and Migration of Cultured Primary Newborn Rat Lung Fibroblasts

“…Mek gene inactivation in the lung mesenchyme caused lung hypoplasia and tracheal defects because of increased apoptosis and reduced branching. Moreover, it indicated that ERK potentially interacts with the Wnt pathway during lung development [ 31 ]. The appearance of pulmonary dysplasia is characterized by reduced branching, increased apoptosis, and decreased mesenchymal cell proliferation.…”

Association of the proliferation of lung fibroblasts with the ERK1/2 signaling pathway in neonatal rats with hyperoxia‑induced lung fibrosis

“…Inactivation of both Mek genes in epithelial cells causes lung agenesis and may be fatal, and mutant Mek genes in mesenchymal cells present as lung hypoplasia, tracheal defects and neonatal death, but not kyphosis and omphalocele (31). Expression studies have indicated potential interactions of the ERK and Wnt signaling pathways during lung development (32). Dermo1 Cre -deletion rats are deficient in the mesenchyme-specific Mek gene function, which is associated with intrauterine growth restriction, giant omphalocele, kyphosis, lung hypoplasia, altered trachea patterning and still birth (33).…”