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Nephronectin is required to maintain right lung lobar separation during embryonic development.

Carole L Wilson1, Chi F Hung2, Brian M Burkel3

  • 1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, University of Wisconsin, Madison, Wisconsin, United States.

American Journal of Physiology. Lung Cellular and Molecular Physiology
|January 31, 2023
PubMed
Summary

Nephronectin (NPNT) is crucial for lung development, as its absence causes right lung lobe fusion in mice. This suggests NPNT signaling maintains lung lobe separation during embryogenesis.

Keywords:
basement membraneembryogenesismesotheliumvisceral pleura

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Area of Science:

  • Developmental Biology
  • Extracellular Matrix Biology
  • Pulmonary Medicine

Background:

  • Nephronectin (NPNT) is a basement membrane protein essential for kidney development.
  • NPNT's role in lung development has not been previously investigated.
  • NPNT is a high-affinity ligand for integrin α8β1.

Purpose of the Study:

  • To investigate the role of Nephronectin (NPNT) in mouse lung development.
  • To determine the consequences of NPNT deficiency on lung morphogenesis.
  • To elucidate the molecular mechanisms underlying NPNT's function in the embryonic lung.

Main Methods:

  • Generation of global NPNT knockout (KO) mice using floxed alleles.
  • Analysis of staged embryonic lung development (E13.5 onwards).
  • Single-cell RNA-seq analysis to identify NPNT-expressing cells and assess gene expression changes in KO lungs.

Main Results:

  • NPNT deficiency led to the fusion of right lung lobes, persisting into adulthood.
  • Abnormalities in basement membrane (laminin α5, collagen IV) and stromal collagen fibrils were observed in KO embryonic lungs.
  • Ex vivo culture of KO embryonic lung lobes demonstrated fusion, with loss of the mesothelial marker Wilms tumor 1 at fusion sites.

Conclusions:

  • NPNT signaling, likely via integrin α8 in the visceral pleura, is essential for maintaining right lung lobe separation during mouse embryogenesis.
  • NPNT deficiency results in basement membrane and stromal abnormalities contributing to lung lobe fusion.
  • The findings highlight a novel role for NPNT in pulmonary development and provide insights into mechanisms of lung lobe formation.