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Although mitochondrial dysfunction is a recognised feature, how\n                      <jats:italic>RARS2<\/jats:italic>\n                      deficiency disrupts neural lineage development remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We generated\n                      <jats:italic>rars2<\/jats:italic>\n                      -deficient zebrafish using the clustered regularly interspaced short palindromic repeats\/CRISPR-associated protein 9 (CRISPR\/Cas9) system and performed single-cell RNA sequencing (scRNA-seq) at 48 hours postfertilisation, complemented by immunofluorescence, in situ hybridisation, behavioural assays and ultrastructural analyses. Neural lineage composition, developmental trajectories, intercellular communication and transcriptional programmes were systematically examined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>rars2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      zebrafish displayed impaired survival, locomotor deficits, early mitochondrial ultrastructural damage and marked disruption of neurogenesis. scRNA-seq revealed reduced neuronal populations and expansion of neural progenitor and glial-like cells. Key neurogenic regulators (\n                      <jats:italic>neurod4<\/jats:italic>\n                      ,\n                      <jats:italic>her6<\/jats:italic>\n                      and\n                      <jats:italic>pou3f1<\/jats:italic>\n                      ) were downregulated, whereas glial and stress-associated markers (\n                      <jats:italic>hmgb1a, fabp7a<\/jats:italic>\n                      and\n                      <jats:italic>foxp1b<\/jats:italic>\n                      ) were upregulated. Developmental pathways including Notch and non-canonical Wnt were attenuated while extracellular matrix (ECM), adhesion and inflammatory programmes were activated. Additional trajectory-based analyses supported dysregulated lineage progression characterised by glial programme activation and impaired maintenance of neurogenic differentiation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>RARS2<\/jats:italic>\n                      deficiency disrupts mitochondrial integrity and reprograms neural lineage development through coordinated suppression of neurogenic transcriptional networks and activation of glial\/ECM programmes. These findings provide mechanistic insight into loss-of-function\n                      <jats:italic>RARS2<\/jats:italic>\n                      deficiency and highlight candidate molecular pathways for future therapeutic investigation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2025-111413","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:20:25Z","timestamp":1785432025000},"page":"683-695","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Single-cell transcriptomics identifies neural fate disruption and glial reprogramming caused by\n                    <i>RARS2<\/i>\n                    deficiency"],"prefix":"10.1136","volume":"63","author":[{"given":"Xing","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 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