Disruption of TrkB-mediated signaling induces disassembly of postsynaptic receptor clusters at neuromuscular junctions

Michael Gonzalez; Francis P. Ruggiero; Qiang Chang; Yi Jun Shi; Mark M. Rich; Susan Kraner; Rita J. Balice-Gordon

doi:10.1016/S0896-6273(00)81113-7

Disruption of TrkB-mediated signaling induces disassembly of postsynaptic receptor clusters at neuromuscular junctions

Michael Gonzalez
, Francis P. Ruggiero
, Qiang Chang
, Yi Jun Shi
, Mark M. Rich
, Susan Kraner
, Rita J. Balice-Gordon

Research output: Contribution to journal › Article › peer-review

203 Scopus citations

Abstract

Neurotrophins and tyrosine receptor kinase (Trk) receptors are expressed in skeletal muscle, but it is unclear what functional role Trk-mediated signaling plays during postnatal life. Full-length TrkB (trkB.FL) as well as truncated TrkB (trkB.t1) were found to be localized primarily to the postsynaptic acetylcholine receptor- (AChR-) rich membrane at neuromuscular junctions. In vivo, dominant-negative manipulation of TrkB signaling using adenovirus to overexpress trkB.t1 in mouse sternomastoid muscle fibers resulted in the disassembly of postsynaptic AChR clusters at neuromuscular junctions, similar to that observed in mutant trkB(+/-) mice. When TrkB- mediated signaling was disrupted in cultured myotubes in the absence of motor nerve terminals and Schwann cells, agrin-induced AChR clusters were also disassembled. These results demonstrate a novel role for neurotrophin signaling through TrkB receptors on muscle fibers in the ongoing maintenance of postsynaptic AChR regions.

Original language	English
Pages (from-to)	567-583
Number of pages	17
Journal	Neuron
Volume	24
Issue number	3
DOIs	https://doi.org/10.1016/S0896-6273(00)81113-7
State	Published - Nov 1999

Funding

We thank Dr. M. Barbacid for providing a mouse trkB.t1 cDNA; Dr. S. Feinstein for anti-trkB.FL- and anti-trkB.t1-specific antibodies; Dr. L. Reichardt for anti-TrkB and anti-TrkA polyclonal antibodies; Dr. G. Yancopolous at Regeneron Pharmaceuticals for a mouse TrkA cDNA; J. Harding and Dr. W. Snider for trkB +/− mice; Dr. M. Chao for providing stably transfected PC12-trkB cells; Dr. R. Pittman for providing PC63 cells; A. Young, J. Cardin, and E. Snyder for preliminary immunostaining observations; A. Cannon, S. Gohari, and H. Zhou for technical assistance; and Drs. D. Kopp and K. Personius for helpful discussions. This work was supported by grants from the National Institutes of Health (NS34373, AG13329), a McKnight Neuroscience Scholar award to R. B.-G., and a National Institutes of Health National Research Service Award (NS10745) to M. G.

Funders	Funder number
National Institutes of Health (NIH)	AG13329
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	R29NS034373
McKnight Endowment Fund for Neuroscience	NS10745

ASJC Scopus subject areas

General Neuroscience

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10.1016/S0896-6273(00)81113-7

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title = "Disruption of TrkB-mediated signaling induces disassembly of postsynaptic receptor clusters at neuromuscular junctions",

abstract = "Neurotrophins and tyrosine receptor kinase (Trk) receptors are expressed in skeletal muscle, but it is unclear what functional role Trk-mediated signaling plays during postnatal life. Full-length TrkB (trkB.FL) as well as truncated TrkB (trkB.t1) were found to be localized primarily to the postsynaptic acetylcholine receptor- (AChR-) rich membrane at neuromuscular junctions. In vivo, dominant-negative manipulation of TrkB signaling using adenovirus to overexpress trkB.t1 in mouse sternomastoid muscle fibers resulted in the disassembly of postsynaptic AChR clusters at neuromuscular junctions, similar to that observed in mutant trkB(+/-) mice. When TrkB- mediated signaling was disrupted in cultured myotubes in the absence of motor nerve terminals and Schwann cells, agrin-induced AChR clusters were also disassembled. These results demonstrate a novel role for neurotrophin signaling through TrkB receptors on muscle fibers in the ongoing maintenance of postsynaptic AChR regions.",

author = "Michael Gonzalez and Ruggiero, \{Francis P.\} and Qiang Chang and Shi, \{Yi Jun\} and Rich, \{Mark M.\} and Susan Kraner and Balice-Gordon, \{Rita J.\}",

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AU - Gonzalez, Michael

AU - Ruggiero, Francis P.

AU - Chang, Qiang

AU - Shi, Yi Jun

AU - Rich, Mark M.

AU - Kraner, Susan

AU - Balice-Gordon, Rita J.

PY - 1999/11

Y1 - 1999/11

N2 - Neurotrophins and tyrosine receptor kinase (Trk) receptors are expressed in skeletal muscle, but it is unclear what functional role Trk-mediated signaling plays during postnatal life. Full-length TrkB (trkB.FL) as well as truncated TrkB (trkB.t1) were found to be localized primarily to the postsynaptic acetylcholine receptor- (AChR-) rich membrane at neuromuscular junctions. In vivo, dominant-negative manipulation of TrkB signaling using adenovirus to overexpress trkB.t1 in mouse sternomastoid muscle fibers resulted in the disassembly of postsynaptic AChR clusters at neuromuscular junctions, similar to that observed in mutant trkB(+/-) mice. When TrkB- mediated signaling was disrupted in cultured myotubes in the absence of motor nerve terminals and Schwann cells, agrin-induced AChR clusters were also disassembled. These results demonstrate a novel role for neurotrophin signaling through TrkB receptors on muscle fibers in the ongoing maintenance of postsynaptic AChR regions.

AB - Neurotrophins and tyrosine receptor kinase (Trk) receptors are expressed in skeletal muscle, but it is unclear what functional role Trk-mediated signaling plays during postnatal life. Full-length TrkB (trkB.FL) as well as truncated TrkB (trkB.t1) were found to be localized primarily to the postsynaptic acetylcholine receptor- (AChR-) rich membrane at neuromuscular junctions. In vivo, dominant-negative manipulation of TrkB signaling using adenovirus to overexpress trkB.t1 in mouse sternomastoid muscle fibers resulted in the disassembly of postsynaptic AChR clusters at neuromuscular junctions, similar to that observed in mutant trkB(+/-) mice. When TrkB- mediated signaling was disrupted in cultured myotubes in the absence of motor nerve terminals and Schwann cells, agrin-induced AChR clusters were also disassembled. These results demonstrate a novel role for neurotrophin signaling through TrkB receptors on muscle fibers in the ongoing maintenance of postsynaptic AChR regions.

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Disruption of TrkB-mediated signaling induces disassembly of postsynaptic receptor clusters at neuromuscular junctions

Abstract

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ASJC Scopus subject areas

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