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Girish V. Putcha¹, Charles A. Harris¹, Krista L. Moulder¹, Rachael M. Easton¹, Craig B. Thompson² and Eugene M. Johnson, Jr.¹

¹ Department of Neurology and Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110
² Department of Medicine and Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104

Address correspondence to Eugene M. Johnson, Jr., Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 4566 Scott Avenue, Box 8103, St. Louis, MO 63110. Tel.: (314) 362-3926. Fax: (314) 747-1772. E-mail: ejohnson{at}pcg.wustl.edu

Trophic factor deprivation (TFD)-induced apoptosis in sympathetic neurons requires macromolecular synthesis–dependent BAX translocation, cytochrome c (cyt c) release, and caspase activation. Here, we report the contributions of other intrinsic and extrinsic pathway signals to these processes. Sympathetic neurons expressed all antiapoptotic BCL-2 proteins examined, yet expressed only certain BH3-only and multidomain proapoptotic BCL-2 family members. All coexpressed proapoptotic proteins did not, however, exhibit functional redundancy or compensatory expression, at least in the Bax^-/-, Bak^-/-, Bim^-/-, Bid^-/-, and Bad^-/- neurons examined. Although the subcellular distribution or posttranslational modification of certain BCL-2 proteins changed with TFD, neither transcriptional nor posttranslational mechanisms regulated the expression or subcellular localization of BID, BAD, or BAK in this paradigm. Despite modest induction of Fas and FasL expression, Fas-mediated signaling did not contribute to TFD-induced apoptosis in sympathetic neurons. Similar findings were obtained with K⁺ withdrawal–induced apoptosis in cerebellar granule neurons, a model for activity-dependent neuronal survival in the CNS. Thus, expression alone does not guarantee functional redundancy (or compensation) among BCL-2 family members, and, at least in some cells, extrinsic pathway signaling and certain BH3-only proteins (i.e., BID and BAD) do not contribute to BAX-dependent cyt c release or apoptosis caused by TFD.

Key Words: Bax; Bad; Bid; caspase; Fas

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