The developing olfactory system - merging of the periph- eral and central nervous systems： The olfactory system is responsible for the sense of smell and is comprised of a complex topographic map that regenerates thr...The developing olfactory system - merging of the periph- eral and central nervous systems： The olfactory system is responsible for the sense of smell and is comprised of a complex topographic map that regenerates throughout life. In rodents each olfactory sensory neuron expresses one of N 1,300 odorant receptors with the neurons being distributed mosaically within the epithelium. The axons of the sensory neurons do not maintain near-neighbour relationships and instead project to disparate topographic targets in the olfac- tory bulb within the central nervous system. The develop- ment of the targets relies on the intermingling of the sensory axons with the interneurons, glia and second order neurons of the olfactory bulb. Thus the formation of the olfactory system involves the coordinated integration of the axons of the peripheral olfactory sensory neurons with the cells of the olfactory bulb.展开更多
The seat of human intelligence is the human cerebral cortex,which is responsible for our exceptional cognitive abilities.Identifying principles that lead to the development of the large-sized human cerebral cortex wil...The seat of human intelligence is the human cerebral cortex,which is responsible for our exceptional cognitive abilities.Identifying principles that lead to the development of the large-sized human cerebral cortex will shed light on what makes the human brain and species so special.The remarkable increase in the number of human cortical pyramidal neurons and the size of the human cerebral cortex is mainly because human cortical radial glial cells,primary neural stem cells in the cortex,generate cortical pyramidal neurons for more than 130 days,whereas the same process takes only about 7 days in mice.The molecular mechanisms underlying this difference are largely unknown.Here,we found that bone morphogenic protein 7(BMP7)is expressed by increasing the number of corti-cal radial glial cells during mammalian evolution(mouse,ferret,monkey,and human).BMP7 expression in cortical radial glial cells promotes neurogenesis,inhibits gliogenesis,and thereby increases the length of the neurogenic period,whereas Sonic Hedgehog(SHH)signaling promotes cortical gliogenesis.We demonstrate that BMP7 sign-aling and SHH signaling mutually inhibit each other through regulation of GLI3 repressor formation.We propose that BMP7 drives the evolutionary expansion of the mammalian cortex by increasing the length of the neurogenic period.展开更多
Fishes have remarkable ability to effectively rebuild the structure of nerve cells and nerve fibers after central nervous system injury.However,the underlying mechanism is poorly understood.In order to address this is...Fishes have remarkable ability to effectively rebuild the structure of nerve cells and nerve fibers after central nervous system injury.However,the underlying mechanism is poorly understood.In order to address this issue,we investigated the proliferation and apoptosis of cells in contralateral and ipsilateral optic nerves,after stab wound injury to the eye of an adult trout Oncorhynchus mykiss.Heterogenous population of proliferating cells was investigated at 1 week after injury.TUNEL labeling gave a qualitative and quantitative assessment of apoptosis in the cells of optic nerve of trout 2 days after injury.After optic nerve injury,apoptotic response was investigated,and mass patterns of cell migration were found.The maximal concentration of apoptotic bodies was detected in the areas of mass clumps of cells.It is probably indicative of massive cell death in the area of high phagocytic activity of macrophages/microglia.At 1 week after optic nerve injury,we observed nerve cell proliferation in the trout brain integration centers：the cerebellum and the optic tectum.In the optic tectum,proliferating cell nuclear antigen（PCNA）-immunopositive radial glia-like cells were identified.Proliferative activity of nerve cells was detected in the dorsal proliferative（matrix） area of the cerebellum and in parenchymal cells of the molecular and granular layers whereas local clusters of undifferentiated cells which formed neurogenic niches were observed in both the optic tectum and cerebellum after optic nerve injury.In vitro analysis of brain cells of trout showed that suspension cells compared with monolayer cells retain higher proliferative activity,as evidenced by PCNA immunolabeling.Phase contrast observation showed mitosis in individual cells and the formation of neurospheres which gradually increased during 1–4 days of culture.The present findings suggest that trout can be used as a novel model for studying neuronal regeneration.展开更多
tAstrocytes are the largest glial population in the mammalian brain.However,we have a minimal understanding of astrocyte development,especially fate specification in different regions of the brain.Through lineage trac...tAstrocytes are the largest glial population in the mammalian brain.However,we have a minimal understanding of astrocyte development,especially fate specification in different regions of the brain.Through lineage tracing of the progenitors of the third ventricle(3V)wall via in-utero electroporation in the embryonic mouse brain,we show the fate specification and migration pattern of astrocytes derived from radial glia along the 3V wall.Unexpectedly,radial glia located in different regions along the 3V wall of the diencephalon produce distinct cell types:radial glia in the upper region produce astrocytes and those in the lower region produce neurons in the diencephalon.With genetic fate mapping analysis,we reveal that the first population of astrocytes appears along the zona incerta in the diencephalon.Astrogenesis occurs at an early time point in the dorsal region relative to that in the ventral region of the developing diencephalon.With transcriptomic analysis of the region-specific 3V wall and lateral ventricle(LV)wall,we identified cohorts of differentially-expressed genes in the dorsal 3V wall compared to the ventral 3V wall and LV wall that may regulate astrogenesis in the dorsal diencephalon.Together,these results demonstrate that the generation of astrocytes shows a spatiotemporal pattern in the developing mouse diencephalon.展开更多
The association of neurogenesis and gliogenesis with glioma remains unclear.By conducting single-cell RNA-seq analyses on 26 gliomas,we reported their classification into primitive oligodendrocyte precursor cell(pri-O...The association of neurogenesis and gliogenesis with glioma remains unclear.By conducting single-cell RNA-seq analyses on 26 gliomas,we reported their classification into primitive oligodendrocyte precursor cell(pri-OPC)-like and radial glia(RG)-like tumors and validated it in a public cohort and TCGA glioma.The RG-like tumors exhibited wild-type isocitrate dehydrogenase and tended to carry EGFR mutations,and the pri-OPC-like ones were prone to carrying TP53 mutations.Tumor subclones only in pri-OPC-like tumors showed substantially down-regulated MHC-I genes,suggesting their distinct immune evasion programs.Furthermore,the two subgroups appeared to extensively modulate glioma-infiltrating lymphocytes in distinct manners.Some specific genes not expressed in normal immune cells were found in glioma-infiltrating lymphocytes.For example,glial/glioma stem cell markers OLIG1/PTPRZ1 and B cell-specific receptors IGLC2/IGKC were expressed in pri-OPC-like and RG-like glioma-infiltrating lymphocytes,respectively.Their expression was positively correlated with those of immune checkpoint genes(e.g.,LGALS33)and poor survivals as validated by the increased expression of LGALS3 upon IGKC overexpression in Jurkat cells.This finding indicated a potential inhibitory role in tumor-infiltrating lymphocytes and could provide a new way of cancer immune evasion.展开更多
Development of the central nervous system(CNS)requires progressive differentiation of neural stem cells,which generate a variety of neural progenitors with distinct properties and differentiation potentials in a spati...Development of the central nervous system(CNS)requires progressive differentiation of neural stem cells,which generate a variety of neural progenitors with distinct properties and differentiation potentials in a spatiotemporally restricted manner.The underlying mechanisms of neural progenitor diversification during development started to be unraveled over the past years.We have addressed these questions by v-myc immortaliza-tion method and generation of neural progenitor clones.These clones are served as in vitro models of neural differentiation and cellular tools for transplantation in animal models of neurological disorders including spinal cord injury.In this review,we will discuss features of two neural progenitor types(radial glia and GABAergic interneuron progenitor)and diversification even within each progenitor type.We will also discuss pathophysiol-ogy of spinal cord injury and our ongoing research to address both motor and sensory malfunctions by trans-plantation of these neural progenitors.展开更多
基金supported by an Australian Postgraduate Award to D.A
文摘The developing olfactory system - merging of the periph- eral and central nervous systems： The olfactory system is responsible for the sense of smell and is comprised of a complex topographic map that regenerates throughout life. In rodents each olfactory sensory neuron expresses one of N 1,300 odorant receptors with the neurons being distributed mosaically within the epithelium. The axons of the sensory neurons do not maintain near-neighbour relationships and instead project to disparate topographic targets in the olfac- tory bulb within the central nervous system. The develop- ment of the targets relies on the intermingling of the sensory axons with the interneurons, glia and second order neurons of the olfactory bulb. Thus the formation of the olfactory system involves the coordinated integration of the axons of the peripheral olfactory sensory neurons with the cells of the olfactory bulb.
基金supported by the Ministry of Science and Technology of China (STI2030-2021ZD0202300)National Natural Science Foundation of China (NSFC 31820103006,32070971,32100768,32200776,and 32200792)+1 种基金Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX01)ZJ Lab,and Shanghai Center for Brain Science and Brain-Inspired Technology.
文摘The seat of human intelligence is the human cerebral cortex,which is responsible for our exceptional cognitive abilities.Identifying principles that lead to the development of the large-sized human cerebral cortex will shed light on what makes the human brain and species so special.The remarkable increase in the number of human cortical pyramidal neurons and the size of the human cerebral cortex is mainly because human cortical radial glial cells,primary neural stem cells in the cortex,generate cortical pyramidal neurons for more than 130 days,whereas the same process takes only about 7 days in mice.The molecular mechanisms underlying this difference are largely unknown.Here,we found that bone morphogenic protein 7(BMP7)is expressed by increasing the number of corti-cal radial glial cells during mammalian evolution(mouse,ferret,monkey,and human).BMP7 expression in cortical radial glial cells promotes neurogenesis,inhibits gliogenesis,and thereby increases the length of the neurogenic period,whereas Sonic Hedgehog(SHH)signaling promotes cortical gliogenesis.We demonstrate that BMP7 sign-aling and SHH signaling mutually inhibit each other through regulation of GLI3 repressor formation.We propose that BMP7 drives the evolutionary expansion of the mammalian cortex by increasing the length of the neurogenic period.
基金supported by a grant from President of Russian Federation (No.MD-4318.2015.4)a grant from Program for Basic Research of the Far East Branch of the Russian Academy of Sciences 2015–2017 (No.15-I-6-116,section Ⅲ)DST-INSPIRE Faculty Grant (No.IFA14-LSBM-104) from the Department of Science and Technology (DST),Government of India
文摘Fishes have remarkable ability to effectively rebuild the structure of nerve cells and nerve fibers after central nervous system injury.However,the underlying mechanism is poorly understood.In order to address this issue,we investigated the proliferation and apoptosis of cells in contralateral and ipsilateral optic nerves,after stab wound injury to the eye of an adult trout Oncorhynchus mykiss.Heterogenous population of proliferating cells was investigated at 1 week after injury.TUNEL labeling gave a qualitative and quantitative assessment of apoptosis in the cells of optic nerve of trout 2 days after injury.After optic nerve injury,apoptotic response was investigated,and mass patterns of cell migration were found.The maximal concentration of apoptotic bodies was detected in the areas of mass clumps of cells.It is probably indicative of massive cell death in the area of high phagocytic activity of macrophages/microglia.At 1 week after optic nerve injury,we observed nerve cell proliferation in the trout brain integration centers：the cerebellum and the optic tectum.In the optic tectum,proliferating cell nuclear antigen（PCNA）-immunopositive radial glia-like cells were identified.Proliferative activity of nerve cells was detected in the dorsal proliferative（matrix） area of the cerebellum and in parenchymal cells of the molecular and granular layers whereas local clusters of undifferentiated cells which formed neurogenic niches were observed in both the optic tectum and cerebellum after optic nerve injury.In vitro analysis of brain cells of trout showed that suspension cells compared with monolayer cells retain higher proliferative activity,as evidenced by PCNA immunolabeling.Phase contrast observation showed mitosis in individual cells and the formation of neurospheres which gradually increased during 1–4 days of culture.The present findings suggest that trout can be used as a novel model for studying neuronal regeneration.
基金supported by the National Natural Science Foundation of China(31871477 and 32170971)the Natural Science Foundation of Shanghai(18ZR1403800)the National Key Basic Research Program of China(973 Program,2014CB965001).
文摘tAstrocytes are the largest glial population in the mammalian brain.However,we have a minimal understanding of astrocyte development,especially fate specification in different regions of the brain.Through lineage tracing of the progenitors of the third ventricle(3V)wall via in-utero electroporation in the embryonic mouse brain,we show the fate specification and migration pattern of astrocytes derived from radial glia along the 3V wall.Unexpectedly,radial glia located in different regions along the 3V wall of the diencephalon produce distinct cell types:radial glia in the upper region produce astrocytes and those in the lower region produce neurons in the diencephalon.With genetic fate mapping analysis,we reveal that the first population of astrocytes appears along the zona incerta in the diencephalon.Astrogenesis occurs at an early time point in the dorsal region relative to that in the ventral region of the developing diencephalon.With transcriptomic analysis of the region-specific 3V wall and lateral ventricle(LV)wall,we identified cohorts of differentially-expressed genes in the dorsal 3V wall compared to the ventral 3V wall and LV wall that may regulate astrogenesis in the dorsal diencephalon.Together,these results demonstrate that the generation of astrocytes shows a spatiotemporal pattern in the developing mouse diencephalon.
基金supported by talent startup funding from Fudan University(Nos.JIF101017,SXF101012,and JIF101047)Science Innovation 2030-Brain Science and Brain-Inspired Intelligence Technology Major Project(No.2021ZD0201100 Task 4 and No.2021ZD0201104)from the Ministry of Science and Technology(MOST),China+3 种基金Jinsong Wu was supported by Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01)ZJ Lab,and operating grant of Shanghai Brain Bank technical system(No.16JC1420103)Edwin Wang was supported by Alberta Innovates Translational Chair Program in Cancer Genomics,the Natural Sciences and Engineering Research Council of Canada(NSERC,No.RGPIN-2017-04885)Canadian Foundation of Innovation(No.36655).
文摘The association of neurogenesis and gliogenesis with glioma remains unclear.By conducting single-cell RNA-seq analyses on 26 gliomas,we reported their classification into primitive oligodendrocyte precursor cell(pri-OPC)-like and radial glia(RG)-like tumors and validated it in a public cohort and TCGA glioma.The RG-like tumors exhibited wild-type isocitrate dehydrogenase and tended to carry EGFR mutations,and the pri-OPC-like ones were prone to carrying TP53 mutations.Tumor subclones only in pri-OPC-like tumors showed substantially down-regulated MHC-I genes,suggesting their distinct immune evasion programs.Furthermore,the two subgroups appeared to extensively modulate glioma-infiltrating lymphocytes in distinct manners.Some specific genes not expressed in normal immune cells were found in glioma-infiltrating lymphocytes.For example,glial/glioma stem cell markers OLIG1/PTPRZ1 and B cell-specific receptors IGLC2/IGKC were expressed in pri-OPC-like and RG-like glioma-infiltrating lymphocytes,respectively.Their expression was positively correlated with those of immune checkpoint genes(e.g.,LGALS33)and poor survivals as validated by the increased expression of LGALS3 upon IGKC overexpression in Jurkat cells.This finding indicated a potential inhibitory role in tumor-infiltrating lymphocytes and could provide a new way of cancer immune evasion.
基金supported by grants from the New Jersey Commission on Spinal Cord Research and National Natural Science Foundation of China.
文摘Development of the central nervous system(CNS)requires progressive differentiation of neural stem cells,which generate a variety of neural progenitors with distinct properties and differentiation potentials in a spatiotemporally restricted manner.The underlying mechanisms of neural progenitor diversification during development started to be unraveled over the past years.We have addressed these questions by v-myc immortaliza-tion method and generation of neural progenitor clones.These clones are served as in vitro models of neural differentiation and cellular tools for transplantation in animal models of neurological disorders including spinal cord injury.In this review,we will discuss features of two neural progenitor types(radial glia and GABAergic interneuron progenitor)and diversification even within each progenitor type.We will also discuss pathophysiol-ogy of spinal cord injury and our ongoing research to address both motor and sensory malfunctions by trans-plantation of these neural progenitors.
