Less is known about the connection between the malfunction of betaarrestins and developmental defects as the mice with either of two betaarrestin isoforms knockout appear normal. In order to address the biological function of betaarrestins during developmental process, we generate betaarrestin1/2 double knockout mice. We found that betaarrestin1/2 dual-null mice developed respiratory distress and atelectasis that subsequently caused neonatal death. Morphological examination revealed type II pneumocyte immaturity. Our results indicate that not only betaarrestin1/2 double knockout lung tissue show disturbances in cell proliferation but betaarrestin1 and betaarrestin2 contribute to pulmonary surfactant complex generation during pulmonary maturation. Intra-amniotic delivery of recombinant adenovirus expressing betaarrestin1 or betaarrestin2 enhances surfactant-associated proteins synthesis in vivo. Our mRNA microarray data further reveal that betaarrestin1/2 double knockout results in downregulation of a significant proportion of genes involved in several lung morphogenesis processes. Together, our study demonstrates that betaarrestin1 and betaarrestin2 collaborate in embryonic development processes for epithelial pneumocyte differentiation and lung maturation.
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