Misexpression of MIA disrupts lung morphogenesis and causes neonatal death

Microarray experiments designed to identify genes differentially expressed in the E11.5 lung and trachea showed that melanoma inhibitory activity (Mial) was expressed only in the lung. Mial was abundantly expressed during early lung development, but was virtually absent by the end of gestation. Distal embryonic lung epithelium showed high levels of Mial expression, which was suppressed by treatment with either retinoic acid or the FGF signaling antagonist SU5402. Late-gestation fetuses in which lung epithelial hyperplasia was induced by misexpression of FGF7 or FGF10 showed continued expression of Mial in areas of aberrant morphogenesis. Mial expression was also significantly increased in urethane-induced lung adenomas. Treatment of E 18.5 lung explants with exogenous MIA caused significant reductions in the expression of the lung differentiation markers Sftpa, Sftpb, Sftpc, and Abca3. Bitransgenic mice expressing MIA under the control of the SFTPC promoter after E16.5, the age when Mial is normally silenced, died from respiratory failure at birth with morphologically immature lungs associated with reduced levels of saturated phosphatidylcholine and mature SP-B. Microarray analysis showed significant reductions in the expression of Sftpa, Sftpb, Abca3, Aqp5, Lzp-s, Scd2, and Ayt12 in lungs misexpressing MIA. These results suggest that the silencing of Mial that occurs in late gestation may be required for maturation of the surfactant system. (C) 2008 Elsevier Inc. All rights reserved.