Abstract
Tet (Ten eleven translocation) family proteins-mediated 5-hydroxymethylcytosine (5hmC) is highly enriched in the neuronal system, and is involved in diverse biological processes and diseases. However, the function of 5hmC in astrocyte remains completely unknown. In the present study, we show that Tet1 deficiency alters astrocyte morphology and impairs neuronal function. Specific deletion of Tet1 in astrocyte impairs learning and memory ability of mice. Using 5hmC high-throughput DNA sequencing and RNA sequencing, we present the distribution of 5hmC among genomic features in astrocyte and show that Tet1 deficiency induces differentially hydroxymethylated regions (DhMRs) and alters gene expression. Mechanistically, we found that Tet1 deficiency leads to the abnormal Ca2+ signaling by regulating the expression of GluA1, which can be rescued by ectopic GluA1. Collectively, our findings suggest that Tet1 plays important function in astrocyte physiology by regulating Ca2+ signaling.
Highlights
As the most abundant glial cells in the central nervous system (CNS), astrocytes are involved in regulating the physiology and pathology of the CNS, such as maintaining CNS homeostasis (Allen and Lyons, 2018)
Golgi staining and quantification results showed that the neurons in the hippocampus of adult cKO mice showed shorter dendrites and fewer spines compared to WT mice (Figures 3E,F). These results suggest that the deficiency of Tet1 in astrocyte alters the morphology of astrocytes and inhibits the neuronal development in vitro and in vivo
In the present study we focused on the physiological function of DNA dioxygenase Tet1 in mouse astrocytes
Summary
As the most abundant glial cells in the central nervous system (CNS), astrocytes are involved in regulating the physiology and pathology of the CNS, such as maintaining CNS homeostasis (Allen and Lyons, 2018). The dysfunction of astrocyte can result in behavioral deficits and involves multiple neurodevelopmental and neurodegenerative diseases (Molofsky et al, 2012; Chung et al, 2015; Phatnani and Maniatis, 2015; Sofroniew, 2015; Zuchero and Barres, 2015; Allen and Lyons, 2018; Santello et al, 2019; Valori et al, 2019) Both Rett syndrome and fragile X syndrome are neurodevelopmental disorders caused by mutation of MeCP2 and FMR1, respectively. MeCP2- or FMR1-deficient astrocytes induce abnormal neuronal development, while the restoration of mutant genes in astrocytes can ameliorate behavioral deficits of mice
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