ErbB4 Alternative Splicing Mediates Fetal Mouse Alveolar Type II Cell Differentiation In Vitro

BACKGROUND: Alternative splicing (AS) creates different protein isoforms, an important mechanism regulating cell-specific function. Little is known about AS in lung development, particularly in alveolar type II (ATII) cells. ErbB4 receptor isoforms Jma and Jmb have significant and opposing functions in brain, heart, and lung development and/or disease. However, the regulators of ErbB4 AS are unknown. HYPOTHESIS: ErbB4 AS regulators in fetal mouse ATII cells control its function in ATII maturation. METHODS: Candidate ErbB4 AS regulators were found using in silico analysis. Their developmental expression was studied in fetal mouse ATII cells. The effects of splice factor downregulation and upregulation on ATII maturation was analyzed. RESULTS: ErbB4-Jma increased significantly in ATII cells after gestation E16.5. In silico analysis found four candidate splice factors: FOX2, CUG/CELF1, TIAR and HUB. Fetal ATII cells expressed these factors in distinct developmental profiles. HUB downregulation in E17.5 ATII cells increased Jma isoform levels and Sftpb gene expression, and decreased Jmb. HUB overexpression decreased Jma and Sftpb. CONCLUSIONS: ErbB4 AS is developmentally controlled by HUB in fetal ATII cells, promoting ATII differentiation. Regulated AS expression during ATII cell differentiation suggests novel therapeutic strategies to approach human disease.