Abstract 1308: Achaete-scute homolog 1 (Ascl1) lineage in the lung gives rise to multiple cell types

Abstract Lung contains many highly specialized cells. Type I pneumocytes are responsible for gas exchange, while type II pneumocytes secrete surfactant which prevents alveoli from collapsing. Airways are lined by non-ciliated secretory (Clara) and ciliated cells that eliminate excess mucus and harmful particles, and rare pulmonary neuroendocrine cells (PNECs) which regulate breathing and contribute to carcinogenesis. PNECs have unknown histogenesis but differentiate prior to the other cells. The neural transcription factor achaete-scute homolog 1 (Ascl1) is critical for PNEC development and is associated with stem cell marker expression in normal and neoplastic lung. Hence, we used in vivo lineage and fate tracing strategy to investigate Ascl1-defined cells (ASDCs) during lung development and injury repair. R26R-stop-lacZ (Rosa) reporter mice were crossed with Ascl1-Cre and Ascl1-CreERTM mice, in which the Ascl1 promoter drives the expression of Cre or inducible Cre recombinase, respectively (Battiste et al., Development (2007) 134:285-93). Following recombination, ASDCs and their descendants will be permanently labeled and were further characterized by immunohistochemistry using cellular differentiation markers. Labeled cells in Ascl1-Cre/Rosa mice gave rise not only to PNECs but also to neural, Clara, ciliated, alveolar type I and type II cells. Interestingly, tamoxifen (TM) administration to Ascl1-CreERTM/Rosa dams at embryonic day E9.5 labeled both airway and alveolar cells, while TM injected at E11.5 only labeled airway cells. Moreover, adult Ascl1-CreERTM/Rosa mice were administered TM followed by naphthalene (Nap), which kills Clara cells. It is notable that in addition to PNECs which are resistant to Nap, regenerating Clara cells were now labeled during the injury repair. We conclude that ASDCs are not limited to giving rise to neural cells or PNECs during pulmonary development, but they also contribute to a range of non-neuroendocrine cells such as Clara and ciliated cells as well as alveolar pneumocytes. Further, the lineage participates in injury repair of the airway lining in mature lung. The current Ascl1 lineage study provides a basis for recent studies on mouse small cell lung cancer (Sutherland et al., Cancer Cell (2011) 19:754-64) which suggested that both PNECs and non-neuroendocrine cells such as alveolar type II pneumocytes may serve as progenitors for this very virulent lung cancer type. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1308. doi:1538-7445.AM2012-1308