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Molecular and Cellular Biology, June 2003, p. 4295-4306, Vol. 23, No. 12
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.12.4295-4306.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Targeted Disruption of the Murine Bin1/Amphiphysin II Gene Does Not Disable Endocytosis but Results in Embryonic Cardiomyopathy with Aberrant Myofibril Formation

Alexander J. Muller,1,2 Judith F. Baker,1,{dagger} James B. DuHadaway,1,2 Kai Ge,3,{ddagger} George Farmer,1,§ P. Scott Donover,1,2 Raymond Meade,1,¶ Christian Reid,1 Reinhard Grzanna,1,|| Arthur H. Roach,1,{dagger}{dagger} Neelima Shah,4 Alejandro Peralta Soler,2 and George C. Prendergast1,2,3*

DuPont Pharmaceuticals Company, Wilmington, Delaware,1 Lankenau Institute for Medical Research, Wynnewood,2 Wistar Institute,3 and Biomedical Imaging Core Facility, University of Pennsylvania, Philadelphia, Pennsylvania4

Received 16 August 2002/ Returned for modification 2 September 2002/ Accepted 20 March 2003

The mammalian Bin1/Amphiphysin II gene encodes an assortment of alternatively spliced adapter proteins that exhibit markedly divergent expression and subcellular localization profiles. Bin1 proteins have been implicated in a variety of different cellular processes, including endocytosis, actin cytoskeletal organization, transcription, and stress responses. To gain insight into the physiological functions of the Bin1 gene, we have disrupted it by homologous recombination in the mouse. Bin1 loss had no discernible impact on either endocytosis or phagocytosis in mouse embryo-derived fibroblasts and macrophages, respectively. Similarly, actin cytoskeletal organization, proliferation, and apoptosis in embryo fibroblasts were all unaffected by Bin1 loss. In vivo, however, Bin1 loss resulted in perinatal lethality. Bin1 has been reported to affect muscle cell differentiation and T-tubule formation. No striking histological abnormalities were evident in skeletal muscle of Bin1 null embryos, but severe ventricular cardiomyopathy was observed in these embryos. Ultrastructurally, myofibrils in ventricular cardiomyocytes of Bin1 null embryos were severely disorganized. These results define a developmentally critical role for the Bin1 gene in cardiac muscle development.

* Corresponding author. Mailing address: Lankenau Institute for Medical Research, 100 Lancaster Ave., Wynnewood, PA 19096. Phone: (610) 645-8475. Fax: (610) 645-8091. E-mail: prendergastg{at}mlhs.org.

{dagger} Present address: Johnson and Johnson Pharmaceutical Research and Development, Spring House, Pa.

{ddagger} Present address: Rockefeller University, New York, N.Y.

§ Present address: Fortis Securities, Inc., New York, N.Y.

Present address: Biomedical Imaging Core Facility, University of Pennsylvania, Philadelphia, Pa.

|| Present address: RMG Biosciences, Inc., Woodstock, Md.

{dagger}{dagger} Present address: Serono Pharmaceutical Research Institute, Geneva, Switzerland.

Molecular and Cellular Biology, June 2003, p. 4295-4306, Vol. 23, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.12.4295-4306.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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