Influence of aminoacyl-tRNA synthetase complex-interacting multifunctional protein 1 on epithelial differentiation and organization during lung development

Abstract

Proper development of the respiratory bronchiole and alveolar epithelium proceeds through coordinated crosstalk between the interface of epithelium and neighboring mesenchyme. Signals that facilitate and coordinate the crosstalk as the bronchial forming canalicular stage transitions to construction of air-exchanging, capillary-alveoli niche in the alveolar stage are poorly understood. Expressed within this decisive region, levels of Aminoacyl tRNA Synthetase Complex Interacting Multifunctional Protein 1 (AIMP1) inversely correlates with the maturation of the lung. The present study addresses the role of AIMP1 in lung development through the generation and characterization of Aimp1-/- mutant mice. Mating of Aimp1+/- produced offspring in expected Mendelian ratios throughout embryonic development. However, newborn Aimp1-/- pups exhibited neonatal lethality with mild cyanosis. Imaging both structure and ultrastructure of Aimp1-/- lungs showed disorganized bronchial epithelium, decreased Type I but not Type II cell differentiation, increased distal vessels, and disruption of E-cadherin deposition in cell-cell junctions. Supporting the in vivo findings of disrupted epithelial cell-cell junctions, in vitro biochemical experiments show that a portion of AIMP1 binds to phosphoinositides, the lipid anchor of proteins that have a fundamental role in both cellular membrane and actin cytoskeleton organization; a dramatic disruption in F-actin cytoskeleton was observed in Aimp1-/- mouse embryonic fibroblasts. Such observed structural defects may lead to disrupted cell-cell boundaries. Together, these results suggest a requirement of AIMP1 in epithelial cell differentiation in proper lung development.