Long-term adeno-associated viral vector-mediated expression of truncated TrkB in the adult rat facial nucleus results in motor neuron degeneration.
Adult facial motor neurons continue to express full-length TrkB tyrosine kinase receptor (TrkB.FL), the high-affinity receptor for the neurotrophins BDNF and neurotrophic factor-4/5 (NT-4/5), suggesting that they remain dependent on target-derived and locally produced neurotrophins in adulthood. Studies on the role of TrkB signaling in the adult CNS have been hampered by the early lethality of bdnf, nt-4/5, and trkB knock-out mice. We disrupted TrkB.FL signaling in adult facial motor neurons using adeno-associated viral vector-mediated overexpression of a naturally occurring dominant-negative TrkB receptor, TrkB.T1. Expression of TrkB.T1 resulted in neuronal atrophy and downregulation of NeuN (neuronal-specific nuclear protein) and ChAT expression in facial motor neurons. A subset of transduced neurons displayed signs of motor neuron degeneration that included dendritic beading and rounding of the soma at 2 months of TrkB.T1 expression. Cell counts revealed a significant reduction in motor neuron number in the facial nucleus at 4 months after onset of expression of TrkB.T1, suggesting that a proportion of TrkB.T1-expressing motor neurons became undetectable as a result of severe atrophy or was lost because of cell death. In contrast, overexpression of TrkB.FL did not result in a decrease in facial motor neuron number. Our results indicate that a subset of facial motor neurons remains dependent on TrkB ligands for the maintenance of structural and molecular characteristics in adulthood.
De Wit
Joris
J
Graduate School of Neuroscience, Netherlands Institute for Brain Research, 1105 AZ Amsterdam, The Netherlands.
Eggers
Ruben
R
Evers
Robert
R
Castrén
Eero
E
Verhaagen
Joost
J
D000818:Animals; D001284:Atrophy; D002460:Cell Line; D003712:Dendrites / Q000648:ultrastructure; D000229:Dependovirus / Q000235:genetics*; D015536:Down-Regulation; D005154:Facial Nerve / Q000166:cytology; D015870:Gene Expression; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D009410:Nerve Degeneration / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017384:Sequence Deletion; D013997:Time Factors
D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D020813:Receptor, trkB