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The Journal of Neuroscience, September 15, 2001, 21(18):7099-7109

Caspases 3 and 9 Send a Pro-Apoptotic Signal from Synapse to Cell Body in Olfactory Receptor Neurons

Catherine M. Cowan¹, Jimmy Thai¹, Stanislaw Krajewski³, John C. Reed³, Donald W. Nicholson⁴, Scott H. Kaufmann², and A. Jane Roskams¹

¹ Centre for Molecular Medicine and Therapeutics, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4, ²  Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Graduate School, Rochester, Minnesota 55905, ³ The Burnham Institute, La Jolla, California 92037, and ⁴ Merck Frosst Centre for Therapeutics, Dorval, Montreal, Quebec, Canada H9R 4P8

Caspase-9, an initiator caspase, and caspase-3, an effector caspase, have been suggested to mediate the terminal stages of neuronal apoptosis, but little is known about their activation in vivo. We examined temporal and spatial aspects of caspase-9 and -3 activation in olfactory receptor neurons (ORNs) undergoing apoptosis after target removal in vivo. After removal of the olfactory bulb, enhanced expression of procaspase-9 and -3 is observed in ORNs, followed by activation initially at the level of the lesion, then in axons, and only later in the ORN soma. We established the amyloid precursor-like protein-2 (APLP2) as a caspase substrate that is cleaved in an identical spatiotemporal pattern, suggesting its cleavage is the result of retrograde propagation of a pro-apoptotic signal in a caudorostral wave from the synapse through the axon to the ORN cell body. A null mutation in caspase-3 causes a change in axonal patterning indicative of an overall developmental expansion of the ORN population, and mature ORNs of caspase-3 knock-outs do not undergo caspase-dependent terminal dUTP nick end labeling-positive apoptosis after olfactory bulb removal. These results demonstrate that ORNs require caspase-3 activation to undergo normal developmental and mature target-deprived apoptosis. In addition, we demonstrate an axonal site of action for caspase-3 and -9 and show that regulation and activation of caspase-3 and -9 leading to apoptosis is a highly ordered process that occurs initially at the presynaptic level and only later at the cell body after deafferentation.

Key words: olfactory receptor neuron; caspases; amyloid precursor-like protein-2; neuronal apoptosis; retrograde signaling; degeneration

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21187099-11$05.00/0

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