Abstract
Mutations in the MECP2 gene cause Rett syndrome (RTT). Bdnf is a MeCP2 target gene; however, its role in RTT pathogenesis is unknown. We examined Bdnf conditional mutant mice for RTT-relevant pathologies and observed that loss of BDNF caused smaller brain size, smaller CA2 neurons, smaller glomerulus size, and a characteristic hindlimb-clasping phenotype. BDNF protein level was reduced in Mecp2 mutant mice, and deletion of Bdnf in Mecp2 mutants caused an earlier onset of RTT-like symptoms. To assess whether this interaction was functional and potentially therapeutically relevant, we increased BDNF expression in the Mecp2 mutant brain with a conditional Bdnf transgene. BDNF overexpression extended the lifespan, rescued a locomotor defect, and reversed an electrophysiological deficit observed in Mecp2 mutants. Our results provide in vivo evidence for a functional interaction between Mecp2 and Bdnf and demonstrate the physiological significance of altered BDNF expression/signaling in RTT disease progression.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Action Potentials / genetics
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Action Potentials / radiation effects
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Animals
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Animals, Newborn
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Behavior, Animal
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Brain / metabolism
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Brain / pathology
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Brain-Derived Neurotrophic Factor / deficiency
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Brain-Derived Neurotrophic Factor / genetics
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Brain-Derived Neurotrophic Factor / metabolism*
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Disease Models, Animal
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Disease Progression
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Electric Stimulation / methods
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Enzyme-Linked Immunosorbent Assay / methods
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Female
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Gene Expression Regulation / genetics
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Humans
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Immunohistochemistry / methods
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In Vitro Techniques
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Male
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Methyl-CpG-Binding Protein 2 / deficiency
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Methyl-CpG-Binding Protein 2 / genetics*
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Mice
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Mice, Knockout
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Motor Activity / genetics
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Mutation / physiology*
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Neurons / physiology
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Organ Size / genetics
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Patch-Clamp Techniques / methods
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RNA, Messenger / metabolism
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Rett Syndrome / genetics*
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Rett Syndrome / metabolism
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Rett Syndrome / physiopathology
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Reverse Transcriptase Polymerase Chain Reaction / methods
Substances
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Brain-Derived Neurotrophic Factor
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Mecp2 protein, mouse
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Methyl-CpG-Binding Protein 2
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RNA, Messenger