{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:49:25Z","timestamp":1790812165905,"version":"4.1.0"},"reference-count":121,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,2,28]],"date-time":"2021-02-28T00:00:00Z","timestamp":1614470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grants-in-Aid from the Japan Society for the Promotion of Science","award":["JP17K07094"],"award-info":[{"award-number":["JP17K07094"]}]},{"name":"Grants-in-Aid from the Japan Society for the Promotion of Science","award":["JP18K06483"],"award-info":[{"award-number":["JP18K06483"]}]},{"name":"Grants-in-Aid from the Japan Society for the Promotion of Science","award":["JP20H03561"],"award-info":[{"award-number":["JP20H03561"]}]},{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare","doi-asserted-by":"publisher","award":["20FC1036"],"award-info":[{"award-number":["20FC1036"]}],"id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["20gm1010002"],"award-info":[{"award-number":["20gm1010002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP20ek0109488"],"award-info":[{"award-number":["JP20ek0109488"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["20bm0804005"],"award-info":[{"award-number":["20bm0804005"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009438","name":"National Center of Neurology and Psychiatry","doi-asserted-by":"publisher","award":["2-5"],"award-info":[{"award-number":["2-5"]}],"id":[{"id":"10.13039\/501100009438","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005694","name":"Hori Sciences and Arts Foundation","doi-asserted-by":"publisher","award":["Year 2017"],"award-info":[{"award-number":["Year 2017"]}],"id":[{"id":"10.13039\/501100005694","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Signal transduction at the neuromuscular junction (NMJ) is affected in many human diseases, including congenital myasthenic syndromes (CMS), myasthenia gravis, Lambert\u2013Eaton myasthenic syndrome, Isaacs\u2019 syndrome, Schwartz\u2013Jampel syndrome, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. The NMJ is a prototypic cholinergic synapse between the motor neuron and the skeletal muscle. Synaptogenesis of the NMJ has been extensively studied, which has also been extrapolated to further understand synapse formation in the central nervous system. Studies of genetically engineered mice have disclosed crucial roles of secreted molecules in the development and maintenance of the NMJ. In this review, we focus on the secreted signaling molecules which regulate the clustering of acetylcholine receptors (AChRs) at the NMJ. We first discuss the signaling pathway comprised of neural agrin and its receptors, low-density lipoprotein receptor-related protein 4 (Lrp4) and muscle-specific receptor tyrosine kinase (MuSK). This pathway drives the clustering of acetylcholine receptors (AChRs) to ensure efficient signal transduction at the NMJ. We also discuss three secreted molecules (Rspo2, Fgf18, and connective tissue growth factor (Ctgf)) that we recently identified in the Wnt\/\u03b2-catenin and fibroblast growth factors (FGF) signaling pathways. The three secreted molecules facilitate the clustering of AChRs by enhancing the agrin-Lrp4-MuSK signaling pathway.<\/jats:p>","DOI":"10.3390\/ijms22052455","type":"journal-article","created":{"date-parts":[[2021,2,28]],"date-time":"2021-02-28T20:43:32Z","timestamp":1614545012000},"page":"2455","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Secreted Signaling Molecules at the Neuromuscular Junction in Physiology and Pathology"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1987-458X","authenticated-orcid":false,"given":"Bisei","family":"Ohkawara","sequence":"first","affiliation":[{"name":"Center for Neurological Diseases and Cancer, Division of Neurogenetics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1351-7602","authenticated-orcid":false,"given":"Mikako","family":"Ito","sequence":"additional","affiliation":[{"name":"Center for Neurological Diseases and Cancer, Division of Neurogenetics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1529-2750","authenticated-orcid":false,"given":"Kinji","family":"Ohno","sequence":"additional","affiliation":[{"name":"Center for Neurological Diseases and Cancer, Division of Neurogenetics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1080\/14728222.2017.1369960","article-title":"Agrin-LRP4-MuSK signaling as a therapeutic target for myasthenia gravis and other neuromuscular disorders","volume":"21","author":"Ohno","year":"2017","journal-title":"Expert Opin. 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