Disruption of Mesenchymal Bmpr1a-Mediated BMP Signaling Causes Congenital Pulmonary Cysts in Mice

Core Concepts

Abrogation of mesenchymal Bmpr1a-mediated BMP signaling disrupts normal lung branching morphogenesis, leading to the formation of prenatal pulmonary cystic lesions.

Abstract

The study investigated the role of mesenchymal BMP signaling in regulating fetal lung development. By specifically deleting the BMP receptor 1a (Bmpr1a) in the lung mesenchyme of mice, the authors found that this disrupted normal lung branching morphogenesis and led to the formation of prenatal pulmonary cystic lesions. Key findings: Deletion of mesenchymal Bmpr1a caused abnormal airway development and subsequent prenatal cystic malformation, resembling features of congenital pulmonary airway malformation (CPAM) in humans. Severe deficiency of airway smooth muscle cells and subepithelial elastin fibers were observed in the cystic airways of the Bmpr1a knockout lungs. Ectopic expression of BMP ligands and perturbation of the Sox2-Sox9 proximal-distal axis in the airway epithelium were detected in the Bmpr1a knockout lungs. The BMP-Bmpr1a-p38 MAPK pathway, rather than the Smad-dependent canonical BMP signaling, was found to be critical in regulating airway smooth muscle development. Deletion of Smad1/5, the major downstream effectors of BMP signaling, did not phenocopy the cystic abnormalities observed in the Bmpr1a knockout lungs. The combined defects in airway smooth muscle and elastin fibers may contribute to the pathogenesis of congenital pulmonary cysts.

Stats

Bmpr1a CKO lungs showed decreased terminal airway branching numbers and increased airway branching tip sizes compared to wildtype controls. Bmpr1a CKO lungs exhibited a significant reduction in the expression of genes involved in the Muscle System Process. Elastin expression was substantially decreased in the Bmpr1a CKO lungs at both the mRNA and protein levels.

Quotes

"Abrogation of mesenchymal Bmpr1a disrupted normal lung branching morphogenesis, leading to the formation of prenatal pulmonary cystic lesions." "Severe deficiency of airway smooth muscle cells and subepithelial elastin fibers were found in the cystic airways of the mesenchymal Bmpr1a knockout lungs." "Ectopic expression of BMP ligands and airway epithelial perturbation of the Sox2-Sox9 proximal-distal axis were detected in the mesenchymal Bmpr1a knockout lungs."

Key Insights Distilled From

Defective mesenchymal Bmpr1a-mediated BMP signaling causes congenital pulmonary cysts

by Luo,Y., Cao,... at www.biorxiv.org 09-27-2023

https://www.biorxiv.org/content/10.1101/2023.09.26.559527v2

Deeper Inquiries

How might the insights from this study on the role of mesenchymal BMP signaling in lung development be leveraged to develop new therapeutic strategies for congenital pulmonary diseases?

The insights from this study on the role of mesenchymal BMP signaling in lung development can be leveraged to develop new therapeutic strategies for congenital pulmonary diseases by targeting the BMP-Bmpr1a-p38 MAPK axis. Understanding the critical role of BMP signaling in regulating airway smooth muscle development and the formation of congenital pulmonary cysts provides a potential target for therapeutic intervention. By modulating the BMP signaling pathway in the lung mesenchyme, it may be possible to promote proper airway smooth muscle differentiation and prevent the development of cystic lung phenotypes. This could involve the development of small molecule inhibitors or activators that target specific components of the BMP signaling pathway to restore normal lung development in cases of congenital pulmonary diseases.

What other signaling pathways or transcriptional regulators might interact with the BMP-Bmpr1a-p38 MAPK axis to coordinately control airway smooth muscle development?

Several other signaling pathways and transcriptional regulators may interact with the BMP-Bmpr1a-p38 MAPK axis to coordinately control airway smooth muscle development. One potential pathway is the TGF-β signaling pathway, which has been shown to crosstalk with BMP signaling in various cellular processes. Additionally, the Wnt signaling pathway, known for its role in tissue development and homeostasis, may interact with BMP signaling to regulate airway smooth muscle differentiation. Transcription factors such as myocardin-related transcription factors (MRTFs) and serum response factor (SRF) are also key regulators of smooth muscle gene expression and could potentially interact with the BMP-Bmpr1a-p38 MAPK axis to control airway smooth muscle development. Further research is needed to elucidate the complex network of signaling pathways and transcriptional regulators involved in this process.

Could the disruption of mesenchymal BMP signaling and the resulting cystic lung phenotype be linked to the pathogenesis of other respiratory disorders beyond congenital pulmonary cysts?

The disruption of mesenchymal BMP signaling and the resulting cystic lung phenotype could potentially be linked to the pathogenesis of other respiratory disorders beyond congenital pulmonary cysts. For example, abnormalities in BMP signaling have been implicated in the pathogenesis of pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease (COPD). Dysregulation of BMP signaling in the lung mesenchyme could lead to aberrant airway smooth muscle development, altered extracellular matrix composition, and impaired epithelial differentiation, contributing to the pathogenesis of these respiratory disorders. Understanding the role of BMP signaling in lung development and disease could provide valuable insights into the molecular mechanisms underlying a range of respiratory conditions and inform the development of targeted therapeutic strategies for these disorders.