title: Caspases 3 and 9 send a pro-apoptotic signal from synapse to cell body in olfactory receptor neurons.
abstract: 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.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: C M
authors.initials: CM
authors.lastname: Cowan
authors.forename: J
authors.initials: J
authors.lastname: Thai
authors.forename: S
authors.initials: S
authors.lastname: Krajewski
authors.forename: J C
authors.initials: JC
authors.lastname: Reed
authors.forename: D W
authors.initials: DW
authors.lastname: Nicholson
authors.forename: S H
authors.initials: SH
authors.lastname: Kaufmann
authors.forename: A J
authors.initials: AJ
authors.lastname: Roskams
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001369:Axons / Q000378:metabolism; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018034:Olfactory Receptor Neurons / Q000166:cytology / Q000201:enzymology*; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000201:enzymology*
chemical_list: C489697:APLP1 protein, human; D016564:Amyloid beta-Protein Precursor; C078201:Aplp1 protein, mouse; C492952:Aplp2 protein, mouse; D009419:Nerve Tissue Proteins; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases