{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:41:37Z","timestamp":1759970497800,"version":"build-2065373602"},"reference-count":79,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,19]],"date-time":"2025-01-19T00:00:00Z","timestamp":1737244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)","doi-asserted-by":"publisher","award":["2019\/ENW\/00772598"],"award-info":[{"award-number":["2019\/ENW\/00772598"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"name":"INTENSE (LSH)","award":["2019\/ENW\/00772598"],"award-info":[{"award-number":["2019\/ENW\/00772598"]}]},{"name":"DBI2 (NWO-Gravitation)","award":["2019\/ENW\/00772598"],"award-info":[{"award-number":["2019\/ENW\/00772598"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Semaphorin 3A (Sema3A) is an axon guidance molecule, which is also abundant in the adult central nervous system (CNS), particularly in perineuronal nets (PNNs). PNNs are extracellular matrix structures that restrict plasticity. The cellular sources of Sema3A in PNNs are unknown. Most Sema3A-bearing neurons do not express Sema3A mRNA, suggesting that Sema3A may be released from other neurons. Another potential source of Sema3A is the choroid plexus. To identify sources of PNN-associated Sema3A, we focused on the cerebellar nuclei, which contain Sema3A+ PNNs. Cerebellar nuclei neurons receive prominent input from Purkinje cells (PCs), which express high levels of Sema3A mRNA. By using a non-invasive viral vector approach, we overexpressed Cre in PCs, the choroid plexus, or throughout the CNS of Sema3Afl\/fl mice. Knocking out Sema3A in PCs or the choroid plexus was not sufficient to decrease the amount of PNN-associated Sema3A. Alternatively, knocking out Sema3A throughout the CNS induced a decrease in PNN-associated Sema3A. However, motor deficits, microgliosis, and neurodegeneration were observed, which were due to Cre toxicity. Our study represents the first attempt to unravel cellular sources of PNN-associated Sema3A and shows that non-invasive viral-mediated Cre expression throughout the CNS could lead to toxicity, complicating the interpretation of Cre-mediated Sema3A knock-out.<\/jats:p>","DOI":"10.3390\/ijms26020819","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T06:53:32Z","timestamp":1737442412000},"page":"819","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Study on Potential Sources of Perineuronal Net-Associated Sema3A in Cerebellar Nuclei Reveals Toxicity of Non-Invasive AAV-Mediated Cre Expression in the Central Nervous System"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2838-8708","authenticated-orcid":false,"given":"Geoffrey-Alexander","family":"Gimenez","sequence":"first","affiliation":[{"name":"Department of Neuroregeneration, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"},{"name":"Department of Cerebellar Coordination & Cognition, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2758-2318","authenticated-orcid":false,"given":"Maurits","family":"Romijn","sequence":"additional","affiliation":[{"name":"Department of Neuroregeneration, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9658-4586","authenticated-orcid":false,"given":"Jo\u00eblle","family":"van den Herik","sequence":"additional","affiliation":[{"name":"Department of Neuroregeneration, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wouter","family":"Meijer","sequence":"additional","affiliation":[{"name":"Department of Neuroregeneration, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7017-0791","authenticated-orcid":false,"given":"Ruben","family":"Eggers","sequence":"additional","affiliation":[{"name":"Department of Neuroregeneration, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2119-1442","authenticated-orcid":false,"given":"Barbara","family":"Hobo","sequence":"additional","affiliation":[{"name":"Department of Neuroregeneration, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris I.","family":"De Zeeuw","sequence":"additional","affiliation":[{"name":"Department of Cerebellar Coordination & Cognition, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"},{"name":"Department of Neuroscience, Erasmus MC, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9594-1564","authenticated-orcid":false,"given":"Cathrin B.","family":"Canto","sequence":"additional","affiliation":[{"name":"Department of Cerebellar Coordination & Cognition, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joost","family":"Verhaagen","sequence":"additional","affiliation":[{"name":"Department of Neuroregeneration, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"},{"name":"Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1365-7063","authenticated-orcid":false,"given":"Daniela","family":"Carulli","sequence":"additional","affiliation":[{"name":"Department of Neuroregeneration, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1016\/0092-8674(93)90625-Z","article-title":"The Semaphorin Genes Encode a Family of Transmembrane and Secreted Growth Cone Guidance Molecules","volume":"75","author":"Kolodkin","year":"1993","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/0092-8674(93)80064-L","article-title":"Collapsin: A Protein in Brain That Induces the Collapse and Paralysis of Neuronal Growth Cones","volume":"75","author":"Luo","year":"1993","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/(SICI)1097-4547(19980401)52:1<27::AID-JNR4>3.0.CO;2-M","article-title":"Anatomical Distribution of 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