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Adv."],"published-print":{"date-parts":[[2026,6,12]]},"abstract":"<jats:p>\n                    Rett syndrome (RTT) is an X-linked neurological disorder caused by\n                    <jats:italic toggle=\"yes\">MECP2<\/jats:italic>\n                    mutations, creating distinct cellular environments in females (mosaic) versus males (nonmosaic). Despite female patients representing most cases, how mosaicism contributes molecularly to RTT pathogenesis, particularly in presymptomatic stages, remains poorly understood. To address this question, we profiled hippocampal transcriptomes of young female and male RTT mice using bulk and single-nucleus RNA sequencing. We identified a core disease signature of consistently dysregulated genes only in MeCP2\n                    <jats:sup>\u2212<\/jats:sup>\n                    cells across RTT models. Moreover, we uncovered non\u2013cell autonomous effects exclusively in female MeCP2\n                    <jats:sup>+<\/jats:sup>\n                    excitatory neurons, suggesting that these circuits are more vulnerable early in the mosaic RTT environment. The single-nuclei data also revealed an underappreciated MeCP2\n                    <jats:sup>\u2212<\/jats:sup>\n                    interneuron subtype that 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 nonmosaic environments in early RTT pathogenesis.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeb4265","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T17:58:42Z","timestamp":1781114322000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Single-nucleus profiling reveals a core disease signature and cell type\u2013specific vulnerabilities in early Rett syndrome"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1656-3452","authenticated-orcid":true,"given":"Yan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA."},{"name":"Genetics and Genomics program, Baylor College of Medicine, Houston, TX, USA."},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9650-1130","authenticated-orcid":true,"given":"Ashley G.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA."},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guantong","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA."},{"name":"Genetics and Genomics program, Baylor College of Medicine, Houston, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sih-Rong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4789-3104","authenticated-orcid":true,"given":"Jean-Pierre","family":"Revelli","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA."},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5472-7158","authenticated-orcid":true,"given":"Hu","family":"Chen","sequence":"additional","affiliation":[{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX, USA."},{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7608-0831","authenticated-orcid":true,"given":"Zhandong","family":"Liu","sequence":"additional","affiliation":[{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX, USA."},{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0700-3349","authenticated-orcid":true,"given":"Huda Y.","family":"Zoghbi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA."},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX, USA."},{"name":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA."},{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA."},{"name":"Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, 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