Abstract
Autism spectrum disorders (ASD) are associated with mutations of chromodomain-helicase DNA-binding protein 8 (Chd8) and tuberous sclerosis complex 2 (Tsc2). Although these ASD-related genes are detected in glial cells such as microglia, the effect of Chd8 or Tsc2 deficiency on microglial functions and microglia-mediated brain development remains unclear. In this study, we investigated the role of microglial Chd8 and Tsc2 in cytokine expression, phagocytosis activity, and neuro/gliogenesis from neural stem cells (NSCs) in vitro. Chd8 or Tsc2 knockdown in microglia reduced insulin-like growth factor-1(Igf1) expression under lipopolysaccharide (LPS) stimulation. In addition, phagocytosis activity was inhibited by Tsc2 deficiency, microglia-mediated oligodendrocyte development was inhibited, in particular, the differentiation of oligodendrocyte precursor cells to oligodendrocytes was prevented by Chd8 or Tsc2 deficiency. These results suggest that ASD-related gene expression in microglia is involved in oligodendrocyte differentiation, which may contribute to the white matter pathology relating to ASD.
Highlights
Autism spectrum disorders (ASD) are associated with mutations of chromodomain-helicase DNAbinding protein 8 (Chd8) and tuberous sclerosis complex 2 (Tsc[2])
Mice with Chd[8] and Tsc[2] knockdown in microglia show a reduced number of differentiating oligodendrocytes in the carpus callosum, anterior commissure, and striatum. These results indicate that Chd[8] or Tsc[2] in microglia may contribute to white matter pathology in ASD
tumor necrosis factor (Tnf), Il1b, Spp[1] expression were not affected by siRNA treatment, Igf[1] expression was reduced in both the Chd[8] and Tsc[2] siRNA treatment groups compared with the control siRNA treatment group (Fig. 1f–i). These results shows that deficiency in Chd[8] or Tsc[2] in microglia affects expression of Igf[1], but not major pro-inflammatory cytokines
Summary
Autism spectrum disorders (ASD) are associated with mutations of chromodomain-helicase DNAbinding protein 8 (Chd8) and tuberous sclerosis complex 2 (Tsc[2]) These ASD-related genes are detected in glial cells such as microglia, the effect of Chd[8] or Tsc[2] deficiency on microglial functions and microglia-mediated brain development remains unclear. Phagocytosis activity was inhibited by Tsc[2] deficiency, microglia-mediated oligodendrocyte development was inhibited, in particular, the differentiation of oligodendrocyte precursor cells to oligodendrocytes was prevented by Chd[8] or Tsc[2] deficiency These results suggest that ASD-related gene expression in microglia is involved in oligodendrocyte differentiation, which may contribute to the white matter pathology relating to ASD. These observations prompted us to investigate whether ASD-related genes in microglia are involved in neural development associated with ASD27,28
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
