{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T05:02:08Z","timestamp":1782968528546,"version":"3.54.5"},"posted":{"date-parts":[[2025,2,6]]},"group-title":"Neuroscience","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T00:00:00Z","timestamp":1738800000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The purpose of this study was to investigate how Sphingosine-1-phosphate (S1P) signaling regulates glial phenotype, neuroprotection, and reprogramming of M\u00fcller glia (MG) into neurogenic MG-derived progenitor cells (MGPCs) in the adult mouse retina. We found that S1P-related genes were dynamically regulated following retinal damage.\n                  <jats:italic>S1pr1<\/jats:italic>\n                  (encoding S1P receptor 1) and\n                  <jats:italic>Sphk1<\/jats:italic>\n                  (encoding sphingosine kinase 1) are expressed at low levels by resting MG and are rapidly upregulated following acute damage. Overexpression of the neurogenic bHLH transcription factor Ascl1 in MG downregulates\n                  <jats:italic>S1pr1<\/jats:italic>\n                  , and inhibition of Sphk1 and S1pr1\/3 enhances Ascl1-driven differentiation of bipolar-like cells and suppresses glial differentiation. Treatments that activate S1pr1 or increase retinal levels of S1P initiate pro-inflammatory NF\u03baB-signaling in MG, whereas treatments that inhibit S1pr1 or decreased levels of S1P suppress NF\u03baB-signaling in MG in damaged retinas. Conditional knock-out of NF\u03baB-signaling in MG increases glial expression of\n                  <jats:italic>S1pr1<\/jats:italic>\n                  but decreases levels of\n                  <jats:italic>S1pr3<\/jats:italic>\n                  and\n                  <jats:italic>Sphk1<\/jats:italic>\n                  . Conditional knock-out (cKO) of\n                  <jats:italic>S1pr1<\/jats:italic>\n                  in MG, but not\n                  <jats:italic>Sphk1<\/jats:italic>\n                  , enhances the accumulation of immune cells in acutely damaged retinas. cKO of\n                  <jats:italic>S1pr1 i<\/jats:italic>\n                  s neuroprotective to ganglion cells, whereas cKO of\n                  <jats:italic>Sphk1<\/jats:italic>\n                  is neuroprotective to amacrine cells in NMDA-damaged retinas. Consistent with these findings, pharmacological treatments that inhibit S1P receptors or inhibit Sphk1 had protective effects upon inner retinal neurons. We conclude that the S1P-signaling pathway is activated in MG after damage and this pathway acts secondarily to restrict the accumulation of immune cells, impairs neuron survival and suppresses the reprogramming of MG into neurogenic progenitors in the adult mouse retina.\n                <\/jats:p>","DOI":"10.1101\/2025.02.03.636254","type":"posted-content","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T23:35:19Z","timestamp":1738884919000},"source":"Crossref","is-referenced-by-count":1,"title":["Sphingosine-1-phosphate signaling through M\u00fcller glia regulates neuroprotection and the accumulation of immune cells in the rodent retina"],"prefix":"10.64898","author":[{"given":"Olivia","family":"Taylor","sequence":"first","affiliation":[{"name":"Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210, USA"},{"name":"Neuroscience Graduate Program, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5847-4298","authenticated-orcid":false,"given":"Heithem","family":"El-Hodiri","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6123-7405","authenticated-orcid":false,"given":"Andy J.","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041023592926000_2025.02.03.636254v1.1","doi-asserted-by":"publisher","DOI":"10.1080\/09273948.2023.2273963"},{"key":"2026041023592926000_2025.02.03.636254v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09128"},{"key":"2026041023592926000_2025.02.03.636254v1.3","doi-asserted-by":"crossref","first-page":"e22710","DOI":"10.1096\/fj.202201346R","article-title":"S1PR1 signaling attenuates apoptosis of retinal ganglion cells via modulation of cJun\/Bim cascade and Bad phosphorylation in a mouse model of glaucoma","volume":"37","year":"2023","journal-title":"FASEB J"},{"key":"2026041023592926000_2025.02.03.636254v1.4","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.344952"},{"key":"2026041023592926000_2025.02.03.636254v1.5","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0938-24.2024"},{"key":"2026041023592926000_2025.02.03.636254v1.6","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2121-11-45"},{"key":"2026041023592926000_2025.02.03.636254v1.7","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23976"},{"key":"2026041023592926000_2025.02.03.636254v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24056"},{"key":"2026041023592926000_2025.02.03.636254v1.9","doi-asserted-by":"crossref","unstructured":"Campbell, W. 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