{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:29Z","timestamp":1792790369138,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,29]]},"group-title":"Neuroscience","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01NS104021"],"award-info":[{"award-number":["R01NS104021"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["HT9425-23-1-0682"],"award-info":[{"award-number":["HT9425-23-1-0682"]}],"id":[{"id":"https:\/\/ror.org\/03g2zjp07","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Institute of Dental and Craniofacial Research","award":["R01DE031273"],"award-info":[{"award-number":["R01DE031273"]}],"id":[{"id":"https:\/\/ror.org\/004a2wv92","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,29]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Efficient myelin regeneration requires coordinated signaling between oligodendrocyte progenitor cells (OPCs) and the extracellular matrix, yet how specific heparan sulfate sulfation patterns regulate this process remains poorly understood. The extracellular endosulfatases Sulf1 and Sulf2 selectively remove 6-\n                  <jats:italic>O<\/jats:italic>\n                  -sulfate groups from heparan sulfate proteoglycans (HSPGs). We previously demonstrated that these enzymes are highly expressed by OPCs following demyelination and inhibit OPC recruitment, differentiation, and remyelination through activation of BMP and WNT signaling. We investigated whether sulfotransferases that establish 2-\n                  <jats:italic>O<\/jats:italic>\n                  and 6-\n                  <jats:italic>O<\/jats:italic>\n                  sulfation during HSPG biosynthesis regulate remyelination. Using OPC-specific conditional knockout models, deletion of the 2-\n                  <jats:italic>O<\/jats:italic>\n                  sulfotransferase\n                  <jats:italic>Hs2st1<\/jats:italic>\n                  enhanced OPC recruitment, oligodendrocyte differentiation, and remyelination through suppression of BMP and WNT signaling. Loss of 2-\n                  <jats:italic>O<\/jats:italic>\n                  sulfation induced compensatory remodeling of the heparan sulfate glycome, with a marked enrichment of 6-\n                  <jats:italic>O<\/jats:italic>\n                  -sulfated HS species. Conversely, deletion of 6-\n                  <jats:italic>O<\/jats:italic>\n                  sulfotransferases impaired OPC recruitment and differentiation and reversed the\n                  <jats:italic>Hs2st1<\/jats:italic>\n                  phenotype, identifying 6-\n                  <jats:italic>O<\/jats:italic>\n                  sulfation as the dominant functional determinant of remyelination. Together, these findings establish hierarchical control of remyelination by heparan sulfate sulfation, demonstrating that compensatory remodeling of the heparan sulfate glycome governs regenerative signaling following demyelination.\n                <\/jats:p>","DOI":"10.64898\/2026.09.24.754157","type":"posted-content","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:40:22Z","timestamp":1790746822000},"source":"Crossref","is-referenced-by-count":0,"title":["Hierarchical control of remyelination by heparan sulfate sulfation"],"prefix":"10.64898","author":[{"given":"Rupadevi","family":"Muthaiah","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roopa","family":"Ravichandar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA"},{"name":"Neuroscience Program, Jacob\u2019s School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rathnakar","family":"Poddeti","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aneri P.","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhargavi","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trina","family":"Rudra","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ding","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, School of Medicine, Emory University, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagendra K","family":"Rai","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjan","family":"Dutta","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3942-6637","authenticated-orcid":false,"given":"Fraser J.","family":"Sim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA"},{"name":"Neuroscience Program, Jacob\u2019s School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100310100832000_2026.09.24.754157v1.1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3510-14.2015"},{"key":"2026100310100832000_2026.09.24.754157v1.2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200307053"},{"key":"2026100310100832000_2026.09.24.754157v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.21462"},{"key":"2026100310100832000_2026.09.24.754157v1.4","doi-asserted-by":"publisher","DOI":"10.1126\/science.1103709"},{"key":"2026100310100832000_2026.09.24.754157v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nm1279"},{"key":"2026100310100832000_2026.09.24.754157v1.6","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00085.2022"},{"key":"2026100310100832000_2026.09.24.754157v1.7","doi-asserted-by":"crossref","unstructured":"Carlsson P , Kjellen L (2012) Heparin biosynthesis. 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