Abstract
Members of the ciliary neurotrophic factor (CNTF)/leukemia inhibitory factor (LIF)/cardiotrophin gene family are potent survival factors for embryonic and lesioned motoneurons. These factors act via receptor complexes involving gp130 and LIFR-beta and ligand binding leads to activation of various signaling pathways, including phosphorylation of Stat3. The role of Stat3 in neuronal survival was investigated in mice by Cre-mediated gene ablation in motoneurons. Cre is expressed under the neurofilament light chain (NF-L) promoter, starting around E12 when these neurons become dependent on neurotrophic support. Loss of motoneurons during the embryonic period of naturally occurring cell death is not enhanced in NF-L-Cre; Stat3(flox/KO) mice although motoneurons isolated from these mice need higher concentrations of CNTF for maximal survival in culture. In contrast, motoneuron survival is significantly reduced after facial nerve lesion in the adult. These neurons, however, can be rescued by the addition of neurotrophic factors, including CNTF. Stat3 is essential for upregulation of Reg-2 and Bcl-xl expression in lesioned motoneurons. Our data show that Stat3 activation plays an essential role for motoneuron survival after nerve lesion in postnatal life but not during embryonic development, indicating that signaling requirements for motoneuron survival change during maturation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging
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Animals
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Animals, Newborn
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Axotomy
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Calcium-Binding Proteins / metabolism
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Cell Death / drug effects
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Cell Survival
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Cells, Cultured
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Ciliary Neurotrophic Factor / pharmacology
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism*
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Facial Nerve Injuries / genetics
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Facial Nerve Injuries / metabolism
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Facial Nerve Injuries / pathology*
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Gene Deletion
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Integrases / genetics
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Integrases / metabolism
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Lithostathine
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Mice
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Mice, Knockout
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Motor Neurons / cytology*
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Motor Neurons / metabolism
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Motor Neurons / pathology
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Nerve Tissue Proteins*
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Nervous System / embryology*
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Nervous System / growth & development
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Nervous System / metabolism
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Nervous System / pathology*
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Neurofilament Proteins / genetics
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Organ Specificity
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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STAT3 Transcription Factor
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Signal Transduction*
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Trans-Activators / genetics*
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Trans-Activators / metabolism*
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Viral Proteins / genetics
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Viral Proteins / metabolism
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bcl-X Protein
Substances
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Bcl2l1 protein, mouse
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Calcium-Binding Proteins
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Ciliary Neurotrophic Factor
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DNA-Binding Proteins
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Lithostathine
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Nerve Tissue Proteins
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Neurofilament Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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Reg1 protein, mouse
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STAT3 Transcription Factor
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Stat3 protein, mouse
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Trans-Activators
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Viral Proteins
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bcl-X Protein
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neurofilament protein L
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Cre recombinase
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Integrases