Anterograde and Retrograde Regulation of Neuromuscular Junction Formation and Aging

Hdl Handle:
http://hdl.handle.net/10675.2/621940
Title:
Anterograde and Retrograde Regulation of Neuromuscular Junction Formation and Aging
Authors:
Zhao, Kai
Abstract:
The neuromuscular junction (NMJ) is a chemical synapse that facilitates the neuronal control of muscle contraction. Proper NMJ formation and maintenance require both anterograde and retrograde signaling. In this study, on one hand, we characterized the role of Yes-associated protein (Yap) in the formation of neuromuscular junction (NMJ). In HSA-Yap-/- mice where Yap was mutated specifically in muscle cells, AChR clusters were smaller and distributed in a broader region in the middle of muscle fibers. In addition, HSA-Yap-/- mice also exhibited remarkable presynaptic deficits including less nerve coverage of the endplates, reduced mEPP frequency and increased paired-pulse facilitation, indicating structural and functional defects. Moreover, muscle Yap mutation prevented reinnervation of denervated muscle fibers and the phenotypes were related to compromised β-catenin signaling. Both NMJ formation and regeneration deficits of HSA-Yap-/- mice were ameliorated by inhibiting β-catenin degradation, further corroborating a role of β-catenin as a downstream molecule of Yap to regulate NMJ formation and regeneration. On the other hand, we showed that Lrp4, a receptor for agrin and critical for NMJ formation and maintenance, was reduced at the protein level in aged mice, which was associated with decreased MuSK tyrosine phosphorylation, suggesting compromised agrin-Lrp4-MuSK signaling in aged muscles. Transgenic expression of Lrp4 in muscles alleviated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. Lrp4 ubiquitination was augmented in aged muscles, suggesting increased Lrp4 degradation as a mechanism for the reduced protein level. We also found that sarcoglycan alpha (SGα) interacted with Lrp4 and delayed Lrp4 degradation in co-transfected HEK293 cells. AAV9-mediated expression of SGα in muscles mitigated Lrp4 degradation and NMJ decline in aged mice. These observations support a model where compromised agrin-Lrp4-MuSK signaling serves as a pathological mechanism of age-related NMJ decline and identify a novel function of SGα in stabilizing Lrp4 for NMJ maintenance in aged mice.
Advisors:
Mei, Lin
Affiliation:
Department of Neuroscience and Regenerative Medicine
Issue Date:
29-Nov-2018
URI:
http://hdl.handle.net/10675.2/621940
Type:
Dissertation
Appears in Collections:
Department of Neuroscience & Regenerative Medicine Theses and Dissertations; Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.advisorMei, Linen
dc.contributor.authorZhao, Kaien
dc.date.accessioned2018-11-29T17:02:34Z-
dc.date.available2018-11-29T17:02:34Z-
dc.date.issued2018-11-29-
dc.identifier.urihttp://hdl.handle.net/10675.2/621940-
dc.description.abstractThe neuromuscular junction (NMJ) is a chemical synapse that facilitates the neuronal control of muscle contraction. Proper NMJ formation and maintenance require both anterograde and retrograde signaling. In this study, on one hand, we characterized the role of Yes-associated protein (Yap) in the formation of neuromuscular junction (NMJ). In HSA-Yap-/- mice where Yap was mutated specifically in muscle cells, AChR clusters were smaller and distributed in a broader region in the middle of muscle fibers. In addition, HSA-Yap-/- mice also exhibited remarkable presynaptic deficits including less nerve coverage of the endplates, reduced mEPP frequency and increased paired-pulse facilitation, indicating structural and functional defects. Moreover, muscle Yap mutation prevented reinnervation of denervated muscle fibers and the phenotypes were related to compromised β-catenin signaling. Both NMJ formation and regeneration deficits of HSA-Yap-/- mice were ameliorated by inhibiting β-catenin degradation, further corroborating a role of β-catenin as a downstream molecule of Yap to regulate NMJ formation and regeneration. On the other hand, we showed that Lrp4, a receptor for agrin and critical for NMJ formation and maintenance, was reduced at the protein level in aged mice, which was associated with decreased MuSK tyrosine phosphorylation, suggesting compromised agrin-Lrp4-MuSK signaling in aged muscles. Transgenic expression of Lrp4 in muscles alleviated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. Lrp4 ubiquitination was augmented in aged muscles, suggesting increased Lrp4 degradation as a mechanism for the reduced protein level. We also found that sarcoglycan alpha (SGα) interacted with Lrp4 and delayed Lrp4 degradation in co-transfected HEK293 cells. AAV9-mediated expression of SGα in muscles mitigated Lrp4 degradation and NMJ decline in aged mice. These observations support a model where compromised agrin-Lrp4-MuSK signaling serves as a pathological mechanism of age-related NMJ decline and identify a novel function of SGα in stabilizing Lrp4 for NMJ maintenance in aged mice.-
dc.subjectNeuromuscular Junctionen
dc.subjectAgingen
dc.subjectAnterograde and Retrograde Signalingen
dc.subjectYapen
dc.subjectLrp4en
dc.titleAnterograde and Retrograde Regulation of Neuromuscular Junction Formation and Agingen
dc.typeDissertationen
dc.contributor.departmentDepartment of Neuroscience and Regenerative Medicineen
dc.language.rfc3066en-
dc.date.updated2018-11-29T17:02:35Z-
dc.description.committeeXiong, Wen-Cheng; Lambert, Nevin A; Chen, Bo-Shiun; Zhou, Jiliangen
dc.description.degreeDoctor of Philosophy with a Major in Neuroscienceen
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