Heterozygous loss-of-function variants of FOXP4 are associated with neurodevelopmental disorders(NDDs)that exhibit delayed speech development,intellectual disability,and congenital abnormalities.The etiology of NDDs i...Heterozygous loss-of-function variants of FOXP4 are associated with neurodevelopmental disorders(NDDs)that exhibit delayed speech development,intellectual disability,and congenital abnormalities.The etiology of NDDs is unclear.Here we found that FOXP4 and N-cadherin are expressed in the nuclei and apical end-feet of radial glial cells(RGCs),respectively,in the mouse neocortex during early gestation.Knockdown or dominant-negative inhibition of Foxp4 abolishes the apical condensation of N-cadherin in RGCs and the integrity of neuroepithelium in the ventricular zone(VZ).Inhibition of Foxp4 leads to impeded radial migration of cortical neurons and ectopic neurogenesis from the proliferating VZ.The ectopic differentiation and deficient migration disappear when N-cadherin is over-expressed in RGCs.The data indicate that Foxp4 is essential for N-cadherin-based adherens junctions,the loss of which leads to periventricular heterotopias.We hypothesize that FOXP4 variant-associated NDDs may be caused by disruption of the adherens junctions and malformation of the cerebral cortex.展开更多
Mouse cortical radial glial cells(RGCs)are primary neural stem cells that give rise to cortical oligodendrocytes,astrocytes,and olfactory bulb(OB)GABAergic interneurons in late embryogenesis.There are fundamental gaps...Mouse cortical radial glial cells(RGCs)are primary neural stem cells that give rise to cortical oligodendrocytes,astrocytes,and olfactory bulb(OB)GABAergic interneurons in late embryogenesis.There are fundamental gaps in understanding how these diverse cell subtypes are generated.Here,by combining single-cell RNA-Seq with intersectional lineage analyses,we show that beginning at around E16.5,neocortical RGCs start to generate ASCL1^(+)EGFR^(+)apical multipotent intermediate progenitors(MIPCs),which then differentiate into basal MIPCs that express ASCL1,EGFR,OLIG2,and MKI67.These basal MIPCs undergo several rounds of divisions to generate most of the cortical oligodendrocytes and astrocytes and a subpopulation of OB interneurons.Finally,single-cell ATAC-Seq supported our model for the genetic logic underlying the specification and differentiation of cortical glial cells and OB interneurons.Taken together,this work reveals the process of cortical radial glial cell lineage progression and the developmental origins of cortical astrocytes and oligodendrocytes.展开更多
Hydrogen sulfide(H2S)is considered as a protective factor against cardiovascular disorders.However,there are few reports on the effects of H2S in the central nervous system during stress or injury.Previous studies on ...Hydrogen sulfide(H2S)is considered as a protective factor against cardiovascular disorders.However,there are few reports on the effects of H2S in the central nervous system during stress or injury.Previous studies on goldfish have shown that astrocytic response occurs in the damaged and contralateral optic nerves.Glial fibrillary acidic protein(GFAP)concentration in the optic nerves of rainbow trout has not been measured previously.This study further characterized the astrocytic response in the optic nerve and the brain of a rainbow trout(Oncorhynchus mykiss)after unilateral eye injury and estimated the amount of H2S-producing enzyme cystathionineβ-synthase(CBS)in the brain of the rainbow trout.Within 1 week after unilateral eye injury,a protein band corresponding to a molecular weight of 50 kDa was identified in the ipsi-and contralateral optic nerves of the rainbow trout.The concentration of GFAP in the injured optic nerve increased compared to the protein concentration on the contralateral side.The results of a quantitative analysis of GFAP+cell distribution in the contralateral optic nerve showed the largest number of GFAP+cells and fibers in the optic nerve head.In the damaged optic nerve,patterns of GFAP+cell migration and large GFAP+bipolar activated astrocytes were detected at 1 week after unilateral eye injury.The study of H2S-producing system after unilateral eye injury in the rainbow trout was conducted using enzyme-linked immunosorbent assay,western blot analysis,and immunohistochemistry of polyclonal antibodies again st CBS in the integrative centers of the brain:telencephalon,optic tectum,and cerebellum.Enzyme-linked immunosorbent assay results showed a 1.7-fold increase in CBS expression in the rainbow trout brain at 1 week after unilateral eye injury compared with that in intact animals.In the ventricular and subventricular regions of the rainbow trout telencephalon,CBS+radial glia and neuroepithelial cells were identified.After unilateral eye injury,the number of CBS+neuroepithelial cells in the pallial and subpallial periventricular regions of the telencephalon increased.In the optic tectum,unilateral eye injury led to an increase in CBS expression in radial glial cells;simultaneously,the number of CBS+neuroepithelial cells decreased in intact animals.In the cerebellum of the rainbow trout,neuroglial interrelationships were revealed,where H2S was released,apparently,from astrocyte-like cells.The organization of H2S-producing cell complexes suggests that,the amount of glutamate produced in the rainbow trout cerebellum and its reuptake was controlled by astrocyte-like cells,reducing its excitotoxicity.In the dorsal matrix zone and granular eminences of the rainbow trout cerebellum,CBS was expressed in neuroepithelial cells.After unilateral eye injury,the level of CBS activity increased in all parts of the cerebellum.An increase in the number of H2S-producing cells was a response to oxidative stress after unilateral eye injury,and the overproduction of H2S in the cerebellum occurred to neutralize reactive oxygen species,providing the cells of the rainbow trout cerebellum with a protective effect.A structural reorganization in the dorsal matrix zone,associated with the appearance of an additional CBS+apical zone,and a decrease in the enzyme activity in the dorsal matrix zone,was revealed in the zones of constitutive neurogenesis.All experiments were approved by the Commission on Biomedical Ethics,A.V.Zhirmunsky National Scientific Center of Marine Biology(NSCMB),Far Eastern Branch,Russian Academy of Science(FEB RAS)(approval No.1)on July 31,2019.展开更多
Radial glial cells have two important functions.One is the "scaffolding" of newborn immaturity neurons,leading newborn immaturity neurons move to special area,and form each cortical-layer of central nervous ...Radial glial cells have two important functions.One is the "scaffolding" of newborn immaturity neurons,leading newborn immaturity neurons move to special area,and form each cortical-layer of central nervous system.Another is as an important neural stem cell,which is the main source of neuron and neural glial cells,providing native materials for the growth of central nervous system.This article discusses the history,definition and characters of radial glial cells.展开更多
Brain tumors are the leading cause of cancer death in children,with ependymoma being the third most common and posing a significant clinical burden.Its mechanism of pathogenesis,reliable prognostic indicators,and effe...Brain tumors are the leading cause of cancer death in children,with ependymoma being the third most common and posing a significant clinical burden.Its mechanism of pathogenesis,reliable prognostic indicators,and effective treatments other than surgical resection have all remained elusive.Until recently,ependymoma research was hindered by the small number of tumors available for study,low resolution of cytogenetic techniques,and lack of cell lines and animal models.Ependymoma heterogeneity,which manifests as variations in tumor location,patient age,histological grade,and clinical behavior,together with the observation of a balanced genomic profile in up to 50% of cases,presents additional challenges in understanding the development and progression of this disease.Despite these difficulties,we have made significant headway in the past decade in identifying the genetic alterations and pathways involved in ependymoma tumorigenesis through collaborative efforts and the application of microarray-based genetic(copy number) and transcriptome profiling platforms.Genetic characterization of ependymoma unraveled distinct mRNA-defined subclasses and led to the identification of radial glial cells as its cell type of origin.This review summarizes our current knowledge in the molecular genetics of ependymoma and proposes future research directions necessary to further advance this field.展开更多
Derived from neural stem cells(NSCs)and progenitor cells originated from the neuroectoderm,the nervous system presents an unprecedented degree of cellular diversity,interwoven to ensure correct connections for propaga...Derived from neural stem cells(NSCs)and progenitor cells originated from the neuroectoderm,the nervous system presents an unprecedented degree of cellular diversity,interwoven to ensure correct connections for propagating information and responding to environ-mental cues.NSCs and progenitor cells must integrate cell-intrinsic programs and environmental cues to achieve production of appropriate types of neurons and glia at appropriate times and places during develop-ment.These developmental dynamics are reflected in changes in gene expression,which is regulated by transcription factors and at the epigenetic level.From early commitment of neural lineage to functional plas-ticity in terminal differentiated neurons,epigenetic regulation is involved in every step of neural develop-ment.Here we focus on the recent advance in our un-derstanding of epigenetic regulation on orderly genera-tion of diverse neural cell types in the mammalian nervous system,an important aspect of neural devel-opment and regenerative medicine.展开更多
The process of cortical expansion in the central nerv-ous system is a key step of mammalian brain devel-opment to ensure its physiological function.Radial glial(RG)cells are a glial cell type contributing to this pro-...The process of cortical expansion in the central nerv-ous system is a key step of mammalian brain devel-opment to ensure its physiological function.Radial glial(RG)cells are a glial cell type contributing to this pro-gress as intermediate neural progenitor cells responsi-ble for an increase in the number of cortical neurons.In this review,we discuss the current understanding of RG cells during neurogenesis and provide further in-formation on the mechanisms of neurodevelopmental diseases and stem cell-related brain tumorigenesis.Knowledge of neuronal stem cell and relative diseases will bridge benchmark research through translational studies to clinical therapeutic treatments of these dis-eases.展开更多
Human cortical radial glial cells are primary neural stem cells that give rise to cortical glutaminergic projection pyramidal neurons, glial cells (oligodendrocytes and astrocytes) and olfactory bulb GABAergic interne...Human cortical radial glial cells are primary neural stem cells that give rise to cortical glutaminergic projection pyramidal neurons, glial cells (oligodendrocytes and astrocytes) and olfactory bulb GABAergic interneurons. One of prominent features of the human cortex is enriched with glial cells, but there are major gaps in understanding how these glial cells are generated. Herein, by integrating analysis of published human cortical single-cell RNA-Seq datasets with our immunohistochemistical analyses, we show that around gestational week 18, EGFR-expressing human cortical truncated radial glial cells (tRGs) give rise to basal multipotent intermediate progenitors (bMIPCs) that express EGFR, ASCL1, OLIG2 and OLIG1. These bMIPCs undergo several rounds of mitosis and generate cortical oligodendrocytes, astrocytes and olfactory bulb interneurons. We also characterized molecular features of the cortical tRG. Integration of our findings suggests a general picture of the lineage progression of cortical radial glial cells, a fundamental process of the developing human cerebral cortex.展开更多
基金supported by the Wenzhou Municipal Science and Technology Bureau(Y20210901)the Natural Science Foundation of Zhejiang Province(LQ20H090001)the Scientific Research Fund of Wenling Science and Technology Bureau(2018C320001).
文摘Heterozygous loss-of-function variants of FOXP4 are associated with neurodevelopmental disorders(NDDs)that exhibit delayed speech development,intellectual disability,and congenital abnormalities.The etiology of NDDs is unclear.Here we found that FOXP4 and N-cadherin are expressed in the nuclei and apical end-feet of radial glial cells(RGCs),respectively,in the mouse neocortex during early gestation.Knockdown or dominant-negative inhibition of Foxp4 abolishes the apical condensation of N-cadherin in RGCs and the integrity of neuroepithelium in the ventricular zone(VZ).Inhibition of Foxp4 leads to impeded radial migration of cortical neurons and ectopic neurogenesis from the proliferating VZ.The ectopic differentiation and deficient migration disappear when N-cadherin is over-expressed in RGCs.The data indicate that Foxp4 is essential for N-cadherin-based adherens junctions,the loss of which leads to periventricular heterotopias.We hypothesize that FOXP4 variant-associated NDDs may be caused by disruption of the adherens junctions and malformation of the cerebral cortex.
基金supported by grants from the National Key Research and Development Program of China(2018YFA0108000)the National Natural Science Foundation of China(31630032,31820103006,and 32070971)+1 种基金a Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)ZJLab,and grants from NIH(R01MH094589 and R01NS089777)。
文摘Mouse cortical radial glial cells(RGCs)are primary neural stem cells that give rise to cortical oligodendrocytes,astrocytes,and olfactory bulb(OB)GABAergic interneurons in late embryogenesis.There are fundamental gaps in understanding how these diverse cell subtypes are generated.Here,by combining single-cell RNA-Seq with intersectional lineage analyses,we show that beginning at around E16.5,neocortical RGCs start to generate ASCL1^(+)EGFR^(+)apical multipotent intermediate progenitors(MIPCs),which then differentiate into basal MIPCs that express ASCL1,EGFR,OLIG2,and MKI67.These basal MIPCs undergo several rounds of divisions to generate most of the cortical oligodendrocytes and astrocytes and a subpopulation of OB interneurons.Finally,single-cell ATAC-Seq supported our model for the genetic logic underlying the specification and differentiation of cortical glial cells and OB interneurons.Taken together,this work reveals the process of cortical radial glial cell lineage progression and the developmental origins of cortical astrocytes and oligodendrocytes.
基金supported by a grant from the President of the Russian Federation(No.MD-4318.2015.4 to EVP)a grant from the Program for Basic Research of the Far East Branch of the Russian Academy of Sciences 2015–2017(No.15-I-6-116,section III to EVP,AAV and DKO)
文摘Hydrogen sulfide(H2S)is considered as a protective factor against cardiovascular disorders.However,there are few reports on the effects of H2S in the central nervous system during stress or injury.Previous studies on goldfish have shown that astrocytic response occurs in the damaged and contralateral optic nerves.Glial fibrillary acidic protein(GFAP)concentration in the optic nerves of rainbow trout has not been measured previously.This study further characterized the astrocytic response in the optic nerve and the brain of a rainbow trout(Oncorhynchus mykiss)after unilateral eye injury and estimated the amount of H2S-producing enzyme cystathionineβ-synthase(CBS)in the brain of the rainbow trout.Within 1 week after unilateral eye injury,a protein band corresponding to a molecular weight of 50 kDa was identified in the ipsi-and contralateral optic nerves of the rainbow trout.The concentration of GFAP in the injured optic nerve increased compared to the protein concentration on the contralateral side.The results of a quantitative analysis of GFAP+cell distribution in the contralateral optic nerve showed the largest number of GFAP+cells and fibers in the optic nerve head.In the damaged optic nerve,patterns of GFAP+cell migration and large GFAP+bipolar activated astrocytes were detected at 1 week after unilateral eye injury.The study of H2S-producing system after unilateral eye injury in the rainbow trout was conducted using enzyme-linked immunosorbent assay,western blot analysis,and immunohistochemistry of polyclonal antibodies again st CBS in the integrative centers of the brain:telencephalon,optic tectum,and cerebellum.Enzyme-linked immunosorbent assay results showed a 1.7-fold increase in CBS expression in the rainbow trout brain at 1 week after unilateral eye injury compared with that in intact animals.In the ventricular and subventricular regions of the rainbow trout telencephalon,CBS+radial glia and neuroepithelial cells were identified.After unilateral eye injury,the number of CBS+neuroepithelial cells in the pallial and subpallial periventricular regions of the telencephalon increased.In the optic tectum,unilateral eye injury led to an increase in CBS expression in radial glial cells;simultaneously,the number of CBS+neuroepithelial cells decreased in intact animals.In the cerebellum of the rainbow trout,neuroglial interrelationships were revealed,where H2S was released,apparently,from astrocyte-like cells.The organization of H2S-producing cell complexes suggests that,the amount of glutamate produced in the rainbow trout cerebellum and its reuptake was controlled by astrocyte-like cells,reducing its excitotoxicity.In the dorsal matrix zone and granular eminences of the rainbow trout cerebellum,CBS was expressed in neuroepithelial cells.After unilateral eye injury,the level of CBS activity increased in all parts of the cerebellum.An increase in the number of H2S-producing cells was a response to oxidative stress after unilateral eye injury,and the overproduction of H2S in the cerebellum occurred to neutralize reactive oxygen species,providing the cells of the rainbow trout cerebellum with a protective effect.A structural reorganization in the dorsal matrix zone,associated with the appearance of an additional CBS+apical zone,and a decrease in the enzyme activity in the dorsal matrix zone,was revealed in the zones of constitutive neurogenesis.All experiments were approved by the Commission on Biomedical Ethics,A.V.Zhirmunsky National Scientific Center of Marine Biology(NSCMB),Far Eastern Branch,Russian Academy of Science(FEB RAS)(approval No.1)on July 31,2019.
文摘Radial glial cells have two important functions.One is the "scaffolding" of newborn immaturity neurons,leading newborn immaturity neurons move to special area,and form each cortical-layer of central nervous system.Another is as an important neural stem cell,which is the main source of neuron and neural glial cells,providing native materials for the growth of central nervous system.This article discusses the history,definition and characters of radial glial cells.
文摘Brain tumors are the leading cause of cancer death in children,with ependymoma being the third most common and posing a significant clinical burden.Its mechanism of pathogenesis,reliable prognostic indicators,and effective treatments other than surgical resection have all remained elusive.Until recently,ependymoma research was hindered by the small number of tumors available for study,low resolution of cytogenetic techniques,and lack of cell lines and animal models.Ependymoma heterogeneity,which manifests as variations in tumor location,patient age,histological grade,and clinical behavior,together with the observation of a balanced genomic profile in up to 50% of cases,presents additional challenges in understanding the development and progression of this disease.Despite these difficulties,we have made significant headway in the past decade in identifying the genetic alterations and pathways involved in ependymoma tumorigenesis through collaborative efforts and the application of microarray-based genetic(copy number) and transcriptome profiling platforms.Genetic characterization of ependymoma unraveled distinct mRNA-defined subclasses and led to the identification of radial glial cells as its cell type of origin.This review summarizes our current knowledge in the molecular genetics of ependymoma and proposes future research directions necessary to further advance this field.
基金supported by grants from the National Natural Science Foundation of China(Grant No.2012CB966701)the Ministry of Science and Technology of the People’s Republic of China.
文摘Derived from neural stem cells(NSCs)and progenitor cells originated from the neuroectoderm,the nervous system presents an unprecedented degree of cellular diversity,interwoven to ensure correct connections for propagating information and responding to environ-mental cues.NSCs and progenitor cells must integrate cell-intrinsic programs and environmental cues to achieve production of appropriate types of neurons and glia at appropriate times and places during develop-ment.These developmental dynamics are reflected in changes in gene expression,which is regulated by transcription factors and at the epigenetic level.From early commitment of neural lineage to functional plas-ticity in terminal differentiated neurons,epigenetic regulation is involved in every step of neural develop-ment.Here we focus on the recent advance in our un-derstanding of epigenetic regulation on orderly genera-tion of diverse neural cell types in the mammalian nervous system,an important aspect of neural devel-opment and regenerative medicine.
基金supported by the National Basic Research Program of China(Grant No.2012CB966800)the 1000 Young Talents Program.
文摘The process of cortical expansion in the central nerv-ous system is a key step of mammalian brain devel-opment to ensure its physiological function.Radial glial(RG)cells are a glial cell type contributing to this pro-gress as intermediate neural progenitor cells responsi-ble for an increase in the number of cortical neurons.In this review,we discuss the current understanding of RG cells during neurogenesis and provide further in-formation on the mechanisms of neurodevelopmental diseases and stem cell-related brain tumorigenesis.Knowledge of neuronal stem cell and relative diseases will bridge benchmark research through translational studies to clinical therapeutic treatments of these dis-eases.
基金This work was supported by grants from National Key Research and Development Program of China(2018YFA0108000)National Natural Science Foundation of China(31820103006,31630032,and 32070971)+1 种基金Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)ZJ Lab,and Shanghai Center for Brain Science and Brain-Inspired Technology.We thank Dr.John L.Rubenstein for critical reading of the manuscript.
文摘Human cortical radial glial cells are primary neural stem cells that give rise to cortical glutaminergic projection pyramidal neurons, glial cells (oligodendrocytes and astrocytes) and olfactory bulb GABAergic interneurons. One of prominent features of the human cortex is enriched with glial cells, but there are major gaps in understanding how these glial cells are generated. Herein, by integrating analysis of published human cortical single-cell RNA-Seq datasets with our immunohistochemistical analyses, we show that around gestational week 18, EGFR-expressing human cortical truncated radial glial cells (tRGs) give rise to basal multipotent intermediate progenitors (bMIPCs) that express EGFR, ASCL1, OLIG2 and OLIG1. These bMIPCs undergo several rounds of mitosis and generate cortical oligodendrocytes, astrocytes and olfactory bulb interneurons. We also characterized molecular features of the cortical tRG. Integration of our findings suggests a general picture of the lineage progression of cortical radial glial cells, a fundamental process of the developing human cerebral cortex.
基金supported by grants from the National Natural Science Foundation of China (No.3133003231490591+3 种基金31321091and 61327902)the National Key Basic Research Program of China (No.2014CB910203)the Strategic Priority Research Program of the Chinese Academy of Sciences (No.XDB02040003)
