title: Bcl-xL is an antiapoptotic regulator for postnatal CNS neurons.
abstract: Bcl-xL is a death-inhibiting member of the Bcl-2/Ced9 family of proteins which either promote or inhibit apoptosis. Gene targeting has revealed that Bcl-xL is required for neuronal survival during brain development; however, Bcl-xL knock-out mice do not survive past embryonic day 13.5, precluding an analysis of Bcl-xL function at later stages of development. Bcl-xL expression is maintained at a high level postnatally in the CNS, suggesting that it may also regulate neuron survival in the postnatal period. To explore functions of Bcl-xL related to neuron survival in postnatal life, we generated transgenic mice overexpressing human Bcl-xL under the control of a pan-neuronal promoter. A line that showed strong overexpression in brainstem and a line that showed overexpression in hippocampus and cortex were chosen for analysis. We asked whether overexpression of Bcl-xL influences neuronal survival in the postnatal period by studying two injury paradigms that result in massive neuronal apoptosis. In the standard neonatal facial axotomy paradigm, Bcl-xL overexpression had substantial effects, with survival of 65% of the motor neurons 7 d after axotomy, as opposed to only 15% in nontransgenic littermates. To investigate whether Bcl-xL regulates survival of CNS neurons in the forebrain, we used a hypoxia-ischemia paradigm in neonatal mice. We show here that hypoxia-ischemia leads to substantial apoptosis in the hippocampus and cortex of wild-type neonatal mice. Furthermore, we show that overexpression of Bcl-xL is neuroprotective in this paradigm. We conclude that levels of Bcl-xL in postnatal neurons may be a critical determinant of their susceptibility to apoptosis.
authors.affiliation: Center for the Study of Nervous System Injury, Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Parsadanian
authors.forename: Y
authors.initials: Y
authors.lastname: Cheng
authors.forename: C R
authors.initials: CR
authors.lastname: Keller-Peck
authors.forename: D M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: W D
authors.initials: WD
authors.lastname: Snider
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D019771:Axotomy; D002545:Brain Ischemia / Q000503:physiopathology; D002470:Cell Survival / Q000502:physiology; D002540:Cerebral Cortex / Q000098:blood supply / Q000166:cytology*; D005154:Facial Nerve / Q000166:cytology / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006624:Hippocampus / Q000098:blood supply / Q000166:cytology*; D006801:Humans; D002534:Hypoxia, Brain / Q000503:physiopathology; D007763:Lac Operon; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009474:Neurons / Q000166:cytology* / Q000502:physiology / Q000648:ultrastructure; D016548:Prosencephalon / Q000098:blood supply / Q000166:cytology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes / Q000502:physiology; D051020:bcl-X Protein
chemical_list: C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein