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

• Published in: The Journal of neuroscience 2001-09, Vol.21 (18), p.7099-7109
• Main Authors: Cowan, Catherine M, Thai, Jimmy, Krajewski, Stanislaw, Reed, John C, Nicholson, Donald W, Kaufmann, Scott H, Roskams, A. Jane
• Format: Article
• Language: English
• Subjects: Amyloid beta-Protein Precursor - metabolism; Animals; Apoptosis - physiology; Axons - metabolism; Caspase 3; Caspase 9; Caspases - deficiency; Caspases - genetics; Caspases - metabolism; Enzyme Activation - physiology; Immunohistochemistry; In Situ Nick-End Labeling; Mice; Mice, Knockout; Nerve Tissue Proteins - metabolism; Olfactory Receptor Neurons - cytology; Olfactory Receptor Neurons - enzymology; Signal Transduction - physiology; Synapses - enzymology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.21-18-07099.2001

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.