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J. Biol. Chem., Vol. 282, Issue 33, 23811-23817, August 17, 2007

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ABCA3 Is Critical for Lamellar Body Biogenesis in Vivo^*

Naeun Cheong, Huayan Zhang^¶, Muniswamy Madesh^||, Ming Zhao, Kevin Yu, Chandra Dodia, Aron B. Fisher, Rashmin C. Savani^**, and Henry Shuman¹

From the Department of Physiology, Institute for Environmental Medicine, and ^||Department of Cancer Biology, University of Pennsylvania School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, the ^¶Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, and the ^**Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9063

Mutations in ATP-binding cassette transporter A3 (human ABCA3) protein are associated with fatal respiratory distress syndrome in newborns. We therefore characterized mice with targeted disruption of the ABCA3 gene. Homozygous Abca3^–/– knock-out mice died soon after birth, whereas most of the wild type, Abca3^+/+, and heterozygous, Abca3^+/–, neonates survived. The lungs from E18.5 and E19.5 Abca3^–/– mice were less mature than wild type. Alveolar type 2 cells from Abca3^–/– embryos contained no lamellar bodies, and expression of mature SP-B protein was disrupted when compared with the normal lung surfactant system of wild type embryos. Small structural and functional differences in the surfactant system were seen in adult Abca3^+/– compared with Abca3^+/+ mice. The heterozygotes had fewer lamellar bodies, and the incorporation of radiolabeled substrates into newly synthesized disaturated phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, and phosphatidylserine in both lamellar bodies and surfactant was lower than in Abca3^+/+ mouse lungs. In addition, since the fraction of near term Abca3^–/– embryos was significantly lower than expected from Mendelian inheritance ABCA3 probably plays roles in development unrelated to surfactant. Collectively, these findings strongly suggest that ABCA3 is necessary for lamellar body biogenesis, surfactant protein-B processing, and lung development late in gestation.

Received for publication, May 14, 2007

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Physiology, B400 Richards, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6085. Tel.: 215-573-2757; Fax: 215-898-2654; E-mail: shuman{at}mail.med.upenn.edu.

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