In vivo restoration of physiological levels of truncated TrkB.T1 receptor rescues neuronal cell death in a trisomic mouse model.
Imbalances in neurotrophins or their high-affinity Trk receptors have long been reported in neurodegenerative diseases. However, a molecular link between these gene products and neuronal cell death has not been established. In the trisomy 16 (Ts16) mouse there is increased apoptosis in the cortex, and hippocampal neurons undergo accelerated cell death that cannot be rescued by administration of brain-derived neurotrophic factor (BDNF). Ts16 neurons have normal levels of the TrkB tyrosine kinase receptor but an upregulation of the TrkB.T1 truncated receptor isoform. Here we show that restoration of the physiological level of the TrkB.T1 receptor by gene targeting rescues Ts16 cortical cell and hippocampal neuronal death. Moreover, it corrects resting Ca2+ levels and restores BDNF-induced intracellular signaling mediated by full-length TrkB in Ts16 hippocampal neurons. These data provide a direct link between neuronal cell death and abnormalities in Trk neurotrophin receptor levels.
Dorsey
Susan G
SG
Neural Development Group, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA. sdorsey@son.umaryland.edu
Renn
Cynthia L
CL
Carim-Todd
Laura
L
Barrick
Colleen A
CA
Bambrick
Linda
L
Krueger
Bruce K
BK
Ward
Christopher W
CW
Tessarollo
Lino
L
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D018390:Gene Targeting / Q000379:methods; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D008970:Molecular Weight; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics*; D020127:Recovery of Function / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014314:Trisomy / Q000235:genetics* / Q000503:physiopathology
D019208:Brain-Derived Neurotrophic Factor; D020033:Protein Isoforms; D020813:Receptor, trkB; D002118:Calcium