Caspases 3 and 9 send a pro-apoptotic signal from synapse to cell body in olfactory receptor neurons

Catherine M. Cowan, Jimmy Thai, Stanislaw Krajewski, John C. Reed, Donald W. Nicholson, Scott H. Kaufmann, A. Jane Roskams

Research output: Contribution to journalArticle

105 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7099-7109
Number of pages11
JournalJournal of Neuroscience
Volume21
Issue number18
DOIs
StatePublished - Sep 15 2001

Keywords

  • Amyloid precursor-like protein-2
  • Caspases
  • Degeneration
  • Neuronal apoptosis
  • Olfactory receptor neuron
  • Retrograde signaling

ASJC Scopus subject areas

  • Neuroscience(all)

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