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Betacellulin Overexpression in Transgenic Mice Causes Disproportionate Growth, Pulmonary Hemorrhage Syndrome, and Complex Eye Pathology

Institute of Molecular Animal Breeding and Biotechnology (M.R.S., M.D., I.R.M., E.W.), Gene Center, University of Munich, 81377 Munich, Germany; Institute of Veterinary Pathology (N.H., R.W.), University of Munich, 80539 Munich, Germany; and Institute of Developmental Genetics (C.D., O.P., J.G), GSF-National Research Center for Environment & Health, 85764 Neuherberg, Germany

Address all correspondence and requests for reprints to: Dr. Marlon R. Schneider, Institute of Molecular Animal Breeding and Biotechnology, Gene Center, University of Munich, Feodor-Lynen-Strasse 25, 81377 Munich, Germany. E-mail: schnder{at}lmb.uni-muenchen.de.

The EGF family comprises a network of ligands and receptors that regulate proper development and elicit diverse functions in physiology and pathology. Betacellulin (BTC) is a rather poorly characterized member of the EGF family whose in vivo effects have been linked mainly to endocrine pancreas, intestine, and mammary gland function. In vitro studies revealed that this growth factor is a potent mitogen for diverse cell types and suggested unique receptor-binding properties. Genetic ablation of BTC in mice yielded a mild phenotype, probably because of opportunistic compensation by other EGF receptor ligands. To study the biological capabilities of BTC in vivo, we generated transgenic mice overexpressing BTC ubiquitously, with highest expression levels in heart, lung, brain, and pancreas. Mice overexpressing BTC exhibit high early postnatal mortality, reduced body weight gain, and impaired longitudinal growth. In addition, a variety of pathological alterations were observed. Cataract and abnormally shaped retinal layers as well as bone alterations leading to a dome-shaped, round head form were hallmarks of BTC transgenic mice. The most important finding and the cause of reduced life expectancy of BTC transgenic mice were severe alterations of the lung. Pulmonary pathology was primarily characterized by alveolar hemorrhage, thickening of the alveolar septa, intraalveolar accumulation of hemosiderin-containing macrophages, and nodular pulmonary remodeling. Thus, our model uncovers multiple consequences of BTC overexpression in vivo. These transgenic mice provide a useful model for examining the effects of BTC excess on different organs.

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