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NCNP","award":["2\u22125"],"award-info":[{"award-number":["2\u22125"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Agrin is a heparan sulfate proteoglycan essential for the clustering of acetylcholine receptors at the neuromuscular junction. Neuron\u2212specific isoforms of agrin are generated by alternative inclusion of three exons, called Y, Z8, and Z11 exons, although their processing mechanisms remain elusive. We found, by inspection of splicing cis\u2212elements into the human AGRN gene, that binding sites for polypyrimidine tract binding protein 1 (PTBP1) were extensively enriched around Y and Z exons. PTBP1\u2212silencing enhanced the coordinated inclusion of Y and Z exons in human SH\u2212SY5Y neuronal cells, even though three constitutive exons are flanked by these alternative exons. Deletion analysis using minigenes identified five PTBP1\u2212binding sites with remarkable splicing repression activities around Y and Z exons. Furthermore, artificial tethering experiments indicated that binding of a single PTBP1 molecule to any of these sites represses nearby Y or Z exons as well as the other distal exons. The RRM4 domain of PTBP1, which is required for looping out a target RNA segment, was likely to play a crucial role in the repression. Neuronal differentiation downregulates PTBP1 expression and promotes the coordinated inclusion of Y and Z exons. We propose that the reduction in the PTPB1\u2212RNA network spanning these alternative exons is essential for the generation of the neuron\u2212specific agrin isoforms.<\/jats:p>","DOI":"10.3390\/ijms24087420","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T02:30:03Z","timestamp":1681785003000},"page":"7420","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Neural Isoforms of Agrin Are Generated by Reduced PTBP1\u2212RNA Interaction Network Spanning the Neuron\u2212Specific Splicing Regions in AGRN"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8592-6640","authenticated-orcid":false,"given":"Samira","family":"Bushra","sequence":"first","affiliation":[{"name":"Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichi, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying-Ni","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichi, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atefeh","family":"Joudaki","sequence":"additional","affiliation":[{"name":"Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichi, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1351-7602","authenticated-orcid":false,"given":"Mikako","family":"Ito","sequence":"additional","affiliation":[{"name":"Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichi, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1987-458X","authenticated-orcid":false,"given":"Bisei","family":"Ohkawara","sequence":"additional","affiliation":[{"name":"Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichi, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1529-2750","authenticated-orcid":false,"given":"Kinji","family":"Ohno","sequence":"additional","affiliation":[{"name":"Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichi, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6437-2853","authenticated-orcid":false,"given":"Akio","family":"Masuda","sequence":"additional","affiliation":[{"name":"Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichi, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1083\/jcb.151.1.41","article-title":"Agrin isoforms with distinct amino termini: Differential expression, localization, and function","volume":"151","author":"Burgess","year":"2000","journal-title":"J. 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