The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression.
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.
Chang
Qiang
Q
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Khare
Gargi
G
Dani
Vardhan
V
Nelson
Sacha
S
Jaenisch
Rudolf
R
D000200:Action Potentials / Q000235:genetics / Q000528:radiation effects; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D004558:Electric Stimulation / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D009929:Organ Size / Q000235:genetics; D018408:Patch-Clamp Techniques / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D015518:Rett Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D019208:Brain-Derived Neurotrophic Factor; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D012333:RNA, Messenger