{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T16:56:31Z","timestamp":1789059391098,"version":"build-2803163510"},"posted":{"date-parts":[[2025,6,26]]},"group-title":"Neuroscience","reference-count":72,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:00:00Z","timestamp":1750896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R01NS057819"],"award-info":[{"award-number":["R01NS057819"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["F32N122920-01A1"],"award-info":[{"award-number":["F32N122920-01A1"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Institute of Health","award":["1S10OD016167"],"award-info":[{"award-number":["1S10OD016167"]}]},{"name":"National Institute of Health","award":["HD103555"],"award-info":[{"award-number":["HD103555"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Rett syndrome (RTT) is an X-linked neurological disorder caused by\n                  <jats:italic>MECP2<\/jats:italic>\n                  mutations. Like other X-linked disorders, RTT patients have sex-specific differences in clinical presentation due to distinct cellular environments, where females have \u223c50% of cells expressing either a mutant or wild-type copy of\n                  <jats:italic>MECP2<\/jats:italic>\n                  (mosaic) and males have 100% of cells expressing a mutant\n                  <jats:italic>MECP2<\/jats:italic>\n                  (non-mosaic). Typical RTT females have a short window of normal early development until \u223c6-18 months, followed by regression and progressive decline, whereas neonatal encephalopathy is more likely in RTT males. How these sex-specific differences in cellular context contribute molecularly to RTT pathogenesis, particularly in the presymptomatic stages of RTT females, remains poorly understood. Here, we profiled the hippocampal transcriptomes of female (\n                  <jats:italic>Mecp2<\/jats:italic>\n                  <jats:sup>+\/-<\/jats:sup>\n                  ) and male (\n                  <jats:italic>Mecp2<\/jats:italic>\n                  <jats:sup>-\/y<\/jats:sup>\n                  ) RTT mice at early timepoints using both bulk and single-nucleus RNA-seq, including sorted MeCP2 positive (MeCP2+) and MeCP2 negative (MeCP2-) neurons in female mice. We identified a core disease signature consisting of 12 genes consistently dysregulated only in MeCP2-cells across RTT models. Moreover, we uncovered non-cell-autonomous effects exclusively in female MeCP2+ excitatory neurons, but not inhibitory neurons, suggesting excitatory circuits are more vulnerable early in the mosaic RTT environment. The single-nuclei data also revealed that a previously underappreciated MeCP2-interneuron subtype had the most transcriptional dysregulation in both male and female RTT hippocampi. Together, these data highlight the different effects of MeCP2 loss on excitatory and inhibitory circuits between the mosaic and non-mosaic environment that appear early in RTT pathogenesis.\n                <\/jats:p>","DOI":"10.1101\/2025.06.26.661761","type":"posted-content","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T17:45:15Z","timestamp":1750959915000},"source":"Crossref","is-referenced-by-count":5,"title":["Early transcriptional signatures of MeCP2 positive and negative cells in Rett syndrome"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1656-3452","authenticated-orcid":false,"given":"Yan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX"},{"name":"Genetics and Genomics program, Baylor College of Medicine, Houston, TX"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9650-1130","authenticated-orcid":false,"given":"Ashley G.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangtong","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX"},{"name":"Genetics and Genomics program, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0358-2996","authenticated-orcid":false,"given":"Sih-Rong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Baylor College of Medicine, Houston, TX"},{"name":"Current address: Department of Neurological Surgery, Weill Institute for Neurosciences, University of California, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Revelli","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7608-0831","authenticated-orcid":false,"given":"Zhandong","family":"Liu","sequence":"additional","affiliation":[{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX"},{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0700-3349","authenticated-orcid":false,"given":"Huda Y.","family":"Zoghbi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX"},{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, TX"},{"name":"Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX"},{"name":"Department of Neuroscience, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041210220235000_2025.06.26.661761v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/13810"},{"key":"2026041210220235000_2025.06.26.661761v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(20)30217-9"},{"key":"2026041210220235000_2025.06.26.661761v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22124"},{"key":"2026041210220235000_2025.06.26.661761v1.4","doi-asserted-by":"publisher","DOI":"10.1086\/302690"},{"key":"2026041210220235000_2025.06.26.661761v1.5","doi-asserted-by":"crossref","unstructured":"J. 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