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Loss of BH3-only Protein Bim Inhibits Apoptosis of Hemopoietic Cells in the Fetal Liver and Male Germ Cells but Not Neuronal Cells in Bcl-x–deficient Mice

Rizwan S. Akhtar, Barbara J. Klocke, Andreas Strasser and Kevin A. Roth

Division of Neuropathology, Department of Pathology (RSA,BJK,KAR) and Department of Neurobiology (RSA), University of Alabama–Birmingham, Birmingham, Alabama, and The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia (AS)

Correspondence to: Kevin A. Roth, MD, PhD, Division of Neuropathology, Department of Pathology, University of Alabama–Birmingham SC 961, 1530 3rd Avenue South, Birmingham, AL 35294-0017. E-mail: karoth{at}uab.edu

Members of the Bcl-2 family include pro- and antiapoptotic proteins that regulate programmed cell death of developing tissues and death in response to cellular damage. In developing mice, the antiapoptotic Bcl-x_L is necessary for survival of neural and hematopoietic cells, and consequently, bcl-x–deficient mice die around Day 13.5 of embryogenesis. Furthermore, adult bcl-x^+/– heterozygous male mice have reduced fertility because of testicular degeneration. Bax, a multi-BH (Bcl-2 homology) domain proapoptotic member of the Bcl-2 family, is regulated by Bcl-x_L and is required for the neuropathological abnormalities seen in bcl-x–deficient embryos. The BH3 domain only subgroup of the Bcl-2 family includes proapoptotic members that are essential for the initiation of apoptotic signaling. In this study, we investigated the role for Bim, a BH3 domain only protein, in the embryonic lethality and increased developmental cell death in bcl-x–deficient animals and the perturbed testicular function in bcl-x^+/– adults. Our studies show that bim deficiency attenuates hematopoietic cell death in the fetal liver of bcl-x–deficient animals, indicating that Bim contributes to programmed cell death in this cell population. In addition, we found that testicular degeneration of adult bcl-x^+/– males was rescued by concomitant Bim deficiency. However, concomitant Bim deficiency had no effect on the embryonic lethality and widespread nervous system abnormalities caused by bcl-x deficiency. Our work identifies Bim as an important regulator of bcl-x deficiency–induced cell death during hematopoiesis and testicular development. (J Histochem Cytochem 56:921–927, 2008)

Key Words: Bcl-2 • Bim • apoptosis • neurodegeneration • hematopoiesis • testicular development

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