Journal of medical genetics · 2026
Single-cell transcriptomics identifies neural fate disruption and glial reprogramming caused by RARS2 deficiency.
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Wei Xing, Wang Jing, Wang Yanyun, Zhou Cong, Chen Zhaoyi, Liu Shanling, Sun Huaqin, Zhou Bin, Zhang Lin
Аннотация
BACKGROUND: Pontocerebellar hypoplasia type 6 (PCH6) is caused by biallelic pathogenic variants in RARS2, encoding mitochondrial arginyl-tRNA synthetase. Although mitochondrial dysfunction is a recognised feature, how RARS2 deficiency disrupts neural lineage development remains unclear.
METHODS: We generated rars2-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.
RESULTS: rars2 -/- 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 (neurod4, her6 and pou3f1) were downregulated, whereas glial and stress-associated markers (hmgb1a, fabp7a and foxp1b) 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.
CONCLUSION: RARS2 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 RARS2 deficiency and highlight candidate molecular pathways for future therapeutic investigation.
METHODS: We generated rars2-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.
RESULTS: rars2 -/- 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 (neurod4, her6 and pou3f1) were downregulated, whereas glial and stress-associated markers (hmgb1a, fabp7a and foxp1b) 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.
CONCLUSION: RARS2 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 RARS2 deficiency and highlight candidate molecular pathways for future therapeutic investigation.