TY - JOUR
T1 - Neuregulin1 displayed on motor axons regulates terminal Schwann cell-mediated synapse elimination at developing neuromuscular junctions
AU - Lee, Young Il
AU - Li, Yue
AU - Mikesh, Michelle
AU - Smith, Ian
AU - Nave, Klaus Armin
AU - Schwab, Markus H.
AU - Thompson, Wesley J.
N1 - Funding Information:
We thank Michael Ferns and Takako Sasaki for their gift of antibodies, Carmen Birchmeier and Steve Burden for NRG1 null mutant mice, and Rayna Harris and Hans Hofmann for help with qRT-PCR. This work was supported by National Institutes of Health Grant NS20480 and funds from Texas A&M University.
PY - 2016/1/26
Y1 - 2016/1/26
N2 - Synaptic connections in the nervous system are rearranged during development and in adulthood as a feature of growth, plasticity, aging, and disease. Glia are implicated as active participants in these changes. Here we investigated a signal that controls the participation of peripheral glia, the terminal Schwann cells (SCs), at the neuromuscular junction (NMJ) in mice. Transgenic manipulation of the levels of membrane-tethered neuregulin1 (NRG1-III), a potent activator of SCs normally presented on motor axons, alters the rate of loss of motor inputs at NMJs during developmental synapse elimination. In addition, NMJs of adult transgenic mice that expressed excess axonal NRG1-III exhibited continued remodeling, in contrast to the more stable morphologies of controls. In fact, synaptic SCs of these adult mice with NRG1-III overexpression exhibited behaviors evident in wild type neonates during synapse elimination, including an affinity for the postsynaptic myofiber surface and phagocytosis of nerve terminals. Given that levels of NRG1-III expression normally peak during the period of synapse elimination, our findings identify axon-tethered NRG1 as a molecular determinant for SC-driven neuromuscular synaptic plasticity.
AB - Synaptic connections in the nervous system are rearranged during development and in adulthood as a feature of growth, plasticity, aging, and disease. Glia are implicated as active participants in these changes. Here we investigated a signal that controls the participation of peripheral glia, the terminal Schwann cells (SCs), at the neuromuscular junction (NMJ) in mice. Transgenic manipulation of the levels of membrane-tethered neuregulin1 (NRG1-III), a potent activator of SCs normally presented on motor axons, alters the rate of loss of motor inputs at NMJs during developmental synapse elimination. In addition, NMJs of adult transgenic mice that expressed excess axonal NRG1-III exhibited continued remodeling, in contrast to the more stable morphologies of controls. In fact, synaptic SCs of these adult mice with NRG1-III overexpression exhibited behaviors evident in wild type neonates during synapse elimination, including an affinity for the postsynaptic myofiber surface and phagocytosis of nerve terminals. Given that levels of NRG1-III expression normally peak during the period of synapse elimination, our findings identify axon-tethered NRG1 as a molecular determinant for SC-driven neuromuscular synaptic plasticity.
KW - Neuregulin1
KW - Neuromuscular junction
KW - Schwann cell
KW - Synapse elimination
KW - Synaptic competition
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U2 - 10.1073/pnas.1519156113
DO - 10.1073/pnas.1519156113
M3 - Article
C2 - 26755586
AN - SCOPUS:84955464780
SN - 0027-8424
VL - 113
SP - E479-E487
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 4
ER -