Induction of proneurotrophins and activation of p75NTR-mediated apoptosis via neurotrophin receptor-interacting factor in hippocampal neurons after seizures.
Seizure-induced damage elicits a loss of hippocampal neurons mediated to a great extent by the p75 neurotrophin receptor (NTR). Proneurotrophins, which are potent apoptosis-inducing ligands for p75(NTR), were increased in the hippocampus, particularly in astrocytes, by pilocarpine-induced seizures; and infusion of anti-pro-NGF dramatically attenuated neuronal loss after seizures. The p75(NTR) is expressed in many different cell types in the nervous system, and can mediate a variety of different cellular functions by recruiting specific intracellular binding proteins to activate distinct signaling pathways. In this study, we demonstrate that neurotrophin receptor-interacting factor (NRIF) mediates apoptotic signaling via p75(NTR) in hippocampal neurons in vitro and in vivo. After seizure-induced injury, NRIF(-/-) mice showed an increase in p75(NTR) expression in the hippocampus; however, these neurons failed to undergo apoptosis in contrast to wild-type mice. Treatment of cultured hippocampal neurons with proneurotrophins induced association of NRIF with p75(NTR) and subsequent translocation of NRIF to the nucleus, which was dependent on cleavage of the receptor. Neurons lacking NRIF were resistant to p75(NTR)-mediated apoptosis in vitro and in vivo. In addition, we demonstrate some mechanistic differences in p75(NTR) signaling in hippocampal neurons compared with other cell types. Overall, these studies demonstrate the requirement for NRIF to signal p75(NTR)-mediated apoptosis of hippocampal neurons and that blocking pro-NGF can inhibit neuronal loss after seizures.
Volosin
Marta
M
Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, USA.
Trotter
Christy
C
Cragnolini
Andrea
A
Kenchappa
Rajappa S
RS
Light
Matthew
M
Hempstead
Barbara L
BL
Carter
Bruce D
BD
Friedman
Wilma J
WJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004622:Embryo, Mammalian; D005260:Female; D005452:Fluoresceins; D006624:Hippocampus / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020932:Nerve Growth Factor / Q000134:cerebrospinal fluid*; D009414:Nerve Growth Factors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009930:Organic Chemicals / Q000378:metabolism; D010862:Pilocarpine; D011247:Pregnancy; D011498:Protein Precursors / Q000134:cerebrospinal fluid*; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000473:pathology*; D013997:Time Factors
D004268:DNA-Binding Proteins; D005452:Fluoresceins; D047908:Intracellular Signaling Peptides and Proteins; D009414:Nerve Growth Factors; D009930:Organic Chemicals; D011498:Protein Precursors; D020800:Receptor, Nerve Growth Factor; C402289:Zfp110 protein, mouse; C435731:fluoro jade; C489226:pro-nerve growth factor, mouse; D010862:Pilocarpine; D020932:Nerve Growth Factor