title: Critical role for DP5/Harakiri, a Bcl-2 homology domain 3-only Bcl-2 family member, in axotomy-induced neuronal cell death.
abstract: The survival of neurons is maintained primarily by neurotrophic factors that suppress the apoptotic program. Axotomy or removal of peripheral targets causes neuronal cell death, but the mechanisms involved in the induction of this type of cell death remain poorly understood. Here, we show that DP5/Harakiri, a Bcl-2 homology domain 3-only member of the Bcl-2 family, is induced in motoneurons after transection of the hypoglossal nerve in mice and in sympathetic neurons after nerve growth factor (NGF) withdrawal. To assess the role of DP5 in neuronal cell death, mutant mice deficient in DP5 were generated by gene targeting. DP5-/- mice were viable and exhibited normal postnatal development. Notably, motoneurons from DP5-/- mice were highly protected from cell death induced by resection of the hypoglossal nerve compared with motoneurons from DP5+/+ littermate mice. In addition, deficiency of DP5 in superior cervical ganglia (SCG) neurons resulted in delayed neuronal cell death triggered by NGF withdrawal. Analysis of SCG neurons from DP5-/- mice revealed increased preservation of mitochondrial membrane potential and reduced activation of caspase-3 compared with neurons from wild-type mice. These results indicate that DP5 plays an important role in neuronal cell death induced by axotomy and NGF deprivation through the regulation of mitochondrial function and caspase-3 activation.
authors.affiliation: Division of Structural Cellular Biology, Nara Institute of Science and Technology, Nara 630-0101, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Imaizumi
authors.forename: Adalberto
authors.initials: A
authors.lastname: Benito
authors.forename: Sumiko
authors.initials: S
authors.lastname: Kiryu-Seo
authors.forename: Victor
authors.initials: V
authors.lastname: Gonzalez
authors.forename: Naohiro
authors.initials: N
authors.lastname: Inohara
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyama
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nuñez
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Leiberman
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D019771:Axotomy; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018390:Gene Targeting; D007002:Hypoglossal Nerve / Q000473:pathology / Q000502:physiology; D020437:Hypoglossal Nerve Diseases / Q000378:metabolism / Q000473:pathology; D008526:Medulla Oblongata / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D017385:Sequence Homology
chemical_list: D051017:Apoptosis Regulatory Proteins; C107631:Hrk protein, mouse; D009479:Neuropeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D020932:Nerve Growth Factor; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases