Iron is important for life,and iron deficiency impairs development,but whether the iron level regulates neural differentiation remains elusive.In this study,with iron-regulatory proteins(IRPs)knockout embryonic stem c...Iron is important for life,and iron deficiency impairs development,but whether the iron level regulates neural differentiation remains elusive.In this study,with iron-regulatory proteins(IRPs)knockout embryonic stem cells(ESCs)that showed severe iron deficiency,we found that the Pax6-and Sox2-positive neuronal precursor cells and Tuj1 fibers in IRP1^(-/-)IRP2^(-/-)ESCs were significantly decreased after inducing neural differentiation.Consistently,in vivo study showed that the knockdown of IRP1 in IRP2^(-/-)fetal mice remarkably affected the differentiation of neuronal precursors and the migration of neurons.These findings suggest that low intracellular iron status significantly inhibits neurodifferentiation.When supplementing IRP1^(-/-)IRP2^(-/-)ESCs with iron,these ESCs could differentiate normally.Further investigations revealed that the underlying mechanism was associated with an increase in reactive oxygen species(ROS)production caused by the substantially low level of iron and the downregulation of iron-sulfur cluster protein ISCU,which,in turn,affected the proliferation and differentiation of stem cells.Thus,the appropriate amount of iron is crucial for maintaining normal neural differentiation that is termed ferrodifferentiation.展开更多
Duplications of MECP2-containing genomic segments led to severe autistic symptoms in male. Transgenic mice overexpressing the human MECP2 gene exhibit autistic-like behaviors. Neural circuits underlying social defects...Duplications of MECP2-containing genomic segments led to severe autistic symptoms in male. Transgenic mice overexpressing the human MECP2 gene exhibit autistic-like behaviors. Neural circuits underlying social defects in MECP2 transgenic(MECP2-TG) mice remain unknown. To observe neural activity of MECP2-TG mice in vivo, we performed calcium imaging by implantation of microendoscope in the hippocampal CA1 regions of MECP2-TG and wild type(WT) mice. We identified neurons whose activities were tightly associated with social interaction, which activity patterns were compromised in MECP2-TG mice. Strikingly, we rescued the social-related neural activity in CA1 and social defects in MECP2-TG mice by deleting the human MECP2 transgene using the CRISPR/Cas9 method during adulthood.Our data points to the neural circuitry responsible for social interactions and provides potential therapeutic targets for autism in adulthood.展开更多
基金supported by the National Natural Science Foundation of China(30871260)the Natural Science Foundation of Hebei Province(E2021205003,C2019206575)the Science and Technology Project of Hebei Education Department(QN2019005,BJK2022049)。
文摘Iron is important for life,and iron deficiency impairs development,but whether the iron level regulates neural differentiation remains elusive.In this study,with iron-regulatory proteins(IRPs)knockout embryonic stem cells(ESCs)that showed severe iron deficiency,we found that the Pax6-and Sox2-positive neuronal precursor cells and Tuj1 fibers in IRP1^(-/-)IRP2^(-/-)ESCs were significantly decreased after inducing neural differentiation.Consistently,in vivo study showed that the knockdown of IRP1 in IRP2^(-/-)fetal mice remarkably affected the differentiation of neuronal precursors and the migration of neurons.These findings suggest that low intracellular iron status significantly inhibits neurodifferentiation.When supplementing IRP1^(-/-)IRP2^(-/-)ESCs with iron,these ESCs could differentiate normally.Further investigations revealed that the underlying mechanism was associated with an increase in reactive oxygen species(ROS)production caused by the substantially low level of iron and the downregulation of iron-sulfur cluster protein ISCU,which,in turn,affected the proliferation and differentiation of stem cells.Thus,the appropriate amount of iron is crucial for maintaining normal neural differentiation that is termed ferrodifferentiation.
基金This work was supported by the National Basic Research Program of China(2017YFA0103303)Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32010100,XDB02050400,XDB02050005,XDA16020601)+2 种基金National Basic Research Program of China(2017YFA0102601,2019YFA0110100)National Natural Science Foundation of China(NSFC)(91732301,31671072,31771140,81891001,91432111,81527901,31400977,31625013)Grants of Beijing Brain Initiative of Beijing Municipal Science&Technology Commission(Z181100001518004).
文摘Duplications of MECP2-containing genomic segments led to severe autistic symptoms in male. Transgenic mice overexpressing the human MECP2 gene exhibit autistic-like behaviors. Neural circuits underlying social defects in MECP2 transgenic(MECP2-TG) mice remain unknown. To observe neural activity of MECP2-TG mice in vivo, we performed calcium imaging by implantation of microendoscope in the hippocampal CA1 regions of MECP2-TG and wild type(WT) mice. We identified neurons whose activities were tightly associated with social interaction, which activity patterns were compromised in MECP2-TG mice. Strikingly, we rescued the social-related neural activity in CA1 and social defects in MECP2-TG mice by deleting the human MECP2 transgene using the CRISPR/Cas9 method during adulthood.Our data points to the neural circuitry responsible for social interactions and provides potential therapeutic targets for autism in adulthood.
