Ager-CreER^T2: A New Genetic Tool for Studying Lung Alveolar Development, Homeostasis, and Repair

The alveolar region of the lung is composed of two major epithelial cell types: cuboidal alveolar type 2 cells (AT2 cells), which produce surfactant proteins, and large, thin, alveolar type 1 cells (AT1 cells), specialized for efficient gas exchange. AT1 cells cover more than 95% of the alveolar surface and constitute a major barrier to the entry of pathogenic agents. Relatively few genetic tools are available for studying the development of AT1 cells, the function of genes expressed in them, and the effect of specifically killing them in vivo in the adult lung. One distinguishing feature of AT1 cells is the high level of expression of the gene Ager, encoding the advanced glycation endproduct-specific receptor, a member of the immunoglobulin superfamily of cell surface receptors. In this paper, we report the generation of a novel Ager-CreER^T2 allele in which Cre recombinase is inserted into the first coding exon of the endogenous gene. After treatment with tamoxifen the allele enables Ager⁺ progenitor cells to be efficiently lineage labeled during late embryonic development and AT1 cells to be killed in the adult lung using a Rosa26-diphtheria toxin A allele. Significantly, adult mice in which approximately 50% of the AT1 cells are killed survive the loss; repair is associated with increased proliferation of SFTPC⁺ (surfactant protein C-positive) AT2 cells and the upregulation of Ager expression. The Ager-CreER^T2 allele thus expands the repertoire of genetic tools for studying AT1 turnover, physiology, and repair.