“…including Wnt/β-catenin signaling, coordinate astrocyte specification 9 , the roles of β-catenin cascade in the regulation of astrocyte maturation are not well understood.…”
Section: Introductionmentioning
confidence: 99%
“…During that period astrocytes increase in volume and process complexity, and start expressing markers of functional maturity including gap junction connexins and potassium channels 78 . While multiple developmental pathways, including Wnt/β-catenin signaling, coordinate astrocyte specification 9 , the roles of β-catenin cascade in the regulation of astrocyte maturation are not well understood.…”
Astrocytes play essential roles in supporting neuronal activity and synapse formation; however, mechanisms by which these functions are regulated are unclear. The Wnt/β-catenin signaling pathway plays a crucial role in brain development and is implicated in neurodevelopmental disorders including autism spectrum disorder (ASD). We sought to investigate if some impacts of Wnt signaling are mediated via astrocytes. Here we show that the canonical Wnt/β-catenin pathway is active in postnatal cortical astrocytes and that its effector, the transcription factor TCF7L2 –is expressed in astrocyte lineage cells during embryonic and postnatal development in both mouse and human. Astrocyte-specific deletion of Tcf7l2 in the early postnatal period led to alterations in astrocyte morphology, membrane depolarization and decreased cortical neuron excitability. Mice with the conditional knockout exhibited increased sociability and social preference in a naturalistic setting. Taken together, these data reveal a key role of astrocytic Wnt signaling in shaping postnatal neuronal development and adult social behavior.
“…including Wnt/β-catenin signaling, coordinate astrocyte specification 9 , the roles of β-catenin cascade in the regulation of astrocyte maturation are not well understood.…”
Section: Introductionmentioning
confidence: 99%
“…During that period astrocytes increase in volume and process complexity, and start expressing markers of functional maturity including gap junction connexins and potassium channels 78 . While multiple developmental pathways, including Wnt/β-catenin signaling, coordinate astrocyte specification 9 , the roles of β-catenin cascade in the regulation of astrocyte maturation are not well understood.…”
Astrocytes play essential roles in supporting neuronal activity and synapse formation; however, mechanisms by which these functions are regulated are unclear. The Wnt/β-catenin signaling pathway plays a crucial role in brain development and is implicated in neurodevelopmental disorders including autism spectrum disorder (ASD). We sought to investigate if some impacts of Wnt signaling are mediated via astrocytes. Here we show that the canonical Wnt/β-catenin pathway is active in postnatal cortical astrocytes and that its effector, the transcription factor TCF7L2 –is expressed in astrocyte lineage cells during embryonic and postnatal development in both mouse and human. Astrocyte-specific deletion of Tcf7l2 in the early postnatal period led to alterations in astrocyte morphology, membrane depolarization and decreased cortical neuron excitability. Mice with the conditional knockout exhibited increased sociability and social preference in a naturalistic setting. Taken together, these data reveal a key role of astrocytic Wnt signaling in shaping postnatal neuronal development and adult social behavior.
“…Using our scRNAseq data we optimized previous mouse astrocyte diff erentiation protocols by highlighting and removing non-required transition states and decreasing the overall protocol from 3 weeks to less than 12 days. Our data will be useful for researchers interested in optimizing glial diff erentiations in either species, and provide a window into human glial diff erentiation, which is diffi cult to study given its lateness in development.trolled by a combination of various transcription factors including Nfi a 16,17 , Nfi b 18,19 , Sox9 [20][21][22] , and signaling pathways like Notch 23,24 (reviewed elsewhere [25][26][27][28] ). Studies have begun to uncover regional specifi cations to this process [29][30][31] in line with a recent focus on identifying brain-area specifi c astrocyte subtypes [32][33][34][35] .In humans, much less is understood about the mechanisms directing gliogenesis 27,36 , and neurogenesis more broadly.…”
mentioning
confidence: 99%
“…Our data will be useful for researchers interested in optimizing glial diff erentiations in either species, and provide a window into human glial diff erentiation, which is diffi cult to study given its lateness in development.trolled by a combination of various transcription factors including Nfi a 16,17 , Nfi b 18,19 , Sox9 [20][21][22] , and signaling pathways like Notch 23,24 (reviewed elsewhere [25][26][27][28] ). Studies have begun to uncover regional specifi cations to this process [29][30][31] in line with a recent focus on identifying brain-area specifi c astrocyte subtypes [32][33][34][35] .In humans, much less is understood about the mechanisms directing gliogenesis 27,36 , and neurogenesis more broadly. Even though we understand less about human glial development, there are protocols for human astrocyte diff erentiation that have been verifi ed at the scRNAseq level by comparing gene expression to acutely isolated human astrocytes 37 .…”
mentioning
confidence: 99%
“…trolled by a combination of various transcription factors including Nfi a 16,17 , Nfi b 18,19 , Sox9 [20][21][22] , and signaling pathways like Notch 23,24 (reviewed elsewhere [25][26][27][28] ). Studies have begun to uncover regional specifi cations to this process [29][30][31] in line with a recent focus on identifying brain-area specifi c astrocyte subtypes [32][33][34][35] .…”
Central nervous system macroglia (astrocytes and oligodendrocytes) are required for normal brain development and function, and are among the last cells to emerge during neurodevelopment. Many questions remain about their emergence in the brain and spinal cord, including how early glial fates are specified during development or differen- tiation, and similarly when subtypes of glia are specified. Here, we used single-cell RNA sequencing (scRNAseq) to analyze ~90,000 cells across multiple timepoints during the differentiation of astrocytes and oligodendrocytes from human induced pluripotent stem cells and mouse embryonic stem cells. Using time series analysis of gene expres- sion, we uncovered multiple genes involved in fate specification of glial subtypes in both species. We examined gene expression changes during intermediate states of glial specification, and were able to identify genes that were correlated with the choice between neuron versus glia in both species. Using our scRNAseq data we optimized previous mouse astrocyte differentiation protocols by highlighting and removing non-required transition states and decreasing the overall protocol from 3 weeks to less than 12 days. Our data will be useful for researchers interested in optimizing glial differentiations in either species, and provide a window into human glial differentiation, which is difficult to study given its lateness in development.
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