604. BRAIN DEVELOPMENT IN FRAGILE X SYNDROME: SEX DIFFERENCE AND PARENTAL EPIGENETIC EFFECT IN THE MOUSE MODEL

Abstract Background Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene, which encodes the FMRP protein critical for neurogenesis during cortical development. FXS patients display autistic behaviors and sex-specific differences in brain structure. Aims & Objectives The mechanisms by which Fmr1 deficiency leads to these sex differences during brain development remain unclear. We aim to address whether the transcriptional difference occurs during embryogenesis dependent on FMRP dosage and sex. Method In the present study, we performed bulk RNA sequencing (RNA-seq) using Fmr1-knockout mice at embryonic day 14.5, the peak of neurogenesis. Based on the RNA-seq, we performed clustering analysis and gene set enrichment analysis (GSEA), and identified differentially expressed genes (DEGs) in wild type and Fmr1-knockout mice. Results Clustering analysis revealed gene expression differences influenced by Fmr1 gene dosage and sex. GSEA revealed dysregulated immune system and cell proliferation pathways in female Fmr1-knockout mice, whereas male mutants exhibited disruptions in cell differentiation pathways. DEGs were observed across various cell types, including neural stem cells and neurons. Discussion & Conclusions Our results highlight the significance of sex-dependent transcriptional differences during embryonic development in neurodevelopmental disorders. We are currently investigating parent-of-origin-specific genetic/epigenetic mechanisms in the next generation derived from the FXS mouse model and will discuss further exploration of FMRP’s roles in FXS pathogenesis and symptoms in this symposium.