Human’s robust cognitive abilities,including creativity and language,are made possible,at least in large part,by evolutionary changes made to the cerebral cortex.This paper reviews the biology and evolution of mammal...Human’s robust cognitive abilities,including creativity and language,are made possible,at least in large part,by evolutionary changes made to the cerebral cortex.This paper reviews the biology and evolution of mammalian cortical radial glial cells(primary neural stem cells)and introduces the concept that a genetically step wise process,based on a core molecular pathway already in use,is the evolutionary process that has molded cortical neurogenesis.The core mechanism,which has been identified in our recent studies,is the extracellular signal-regulated kinase(ERK)-bone morphogenic protein 7(BMP7)-GLI3 repressor form(GLI3R)-sonic hedgehog(SHH)positive feedback loop.Additionally,I propose that the molecular basis for cortical evolutionary dwarfism,exemplified by the lissencephalic mouse which originated from a larger gyrencephalic ancestor,is an increase in SHH signaling in radial glia,that antagonizes ERK-BMP7 signaling.Finally,I propose that:(1)SHH signaling is not a key regulator of primate cortical expansion and folding;(2)human cortical radial glial cells do not generate neocortical interneurons;(3)human-specific genes may not be essential for most cortical expansion.I hope this review assists colleagues in the field,guiding research to address gaps in our understanding of cortical development and evolution.展开更多
Objective To investigate the cell proliferation and differentiation in the developing brain of mouse. Methods C57/BL6 mice were divided into 3 groups at random. Bromodeoxyuridine （BrdU） was injected into the brains ...Objective To investigate the cell proliferation and differentiation in the developing brain of mouse. Methods C57/BL6 mice were divided into 3 groups at random. Bromodeoxyuridine （BrdU） was injected into the brains in different development periods once a day for 7 d. The brains were retrieved 4 weeks after the last BrdU injection. Immunohistochemical and immunofluorescent studies were carried out for detecting cell proliferation （BrdU） and cell differentiation （NeuN, APC, lbal, and S 100β）, respectively. Results The number of BrdU labeled cells decreased significantly with the development of the brain. Cell proliferation was prominent in the cortex and striatum. A small portion of BrdU and NeuN double labeled cells could be detected in the cortex at the early stage of development, and in the striatum and CA of the hippocampus in all groups. The majority of BrdU labeled cells were neuroglia, and the number of neuroglia cells decreased dramatically with brain maturation. Neurogenesis is the major cytogenesis in the dentate gyrus. Conclusion These results demonstrated that cell proliferation, differentiation and survival were age and brain region related.展开更多
Precise tuning of gene expression,accomplished by regulato ry networks of transcription factors,epigenetic modifiers,and microRNAs,is crucial for the proper neural development and function of the brain cells.The SOX t...Precise tuning of gene expression,accomplished by regulato ry networks of transcription factors,epigenetic modifiers,and microRNAs,is crucial for the proper neural development and function of the brain cells.The SOX transcription factors are involved in regulating diverse cellular processes during embryonic and adult neurogenesis,such as maintaining the cell stemness,cell prolife ration,cell fate decisions,and terminal diffe rentiation into neurons and glial cells.MicroRNAs represent a class of small non-coding RNAs that play important roles in the regulation of gene expression.Together with other gene regulatory factors,microRNAs regulate different processes during neurogenesis and orchestrate the spatial and temporal expression important for neurodevelopment.The emerging data point to a complex regulatory network between SOX transcription factors and microRNAs that govern distinct cellular activities in the developing and adult brain.Deregulated SOX/mic roRNA interplay in signaling pathways that influence the homeostasis and plasticity in the brain has been revealed in various brain pathologies,including neurodegenerative disorders,traumatic brain injury,and cancer.Therapeutic strategies that target SOX/microRNA interplay have emerged in recent years as a promising tool to target neural tissue regeneration and enhance neuro restoration.N umerous studies have confirmed complex intera ctions between microRNAs and SOX-specific mRNAs regulating key features of glioblastoma.Keeping in mind the crucial roles of SOX genes and microRNAs in neural development,we focus this review on SOX/microRNAs interplay in the brain during development and adulthood in physiological and pathological conditions.Special focus was made on their interplay in brain pathologies to summarize current knowledge and highlight potential future development of molecular therapies.展开更多
Although amyloid-βpeptide is considered neurotoxic,it may mediate several physiological processes during embryonic development and in the adult brain.The pathological function of amyloid-βpeptide has been extensivel...Although amyloid-βpeptide is considered neurotoxic,it may mediate several physiological processes during embryonic development and in the adult brain.The pathological function of amyloid-βpeptide has been extensively studied due to its implication in Alzheimer’s disease,but its physiological function remains poorly understood.Amyloid-βpeptide can be detected in non-aggregated(monomeric)and aggregated(oligomeric and fibrillary)forms.Each form has different cytotoxic and/or physiological properties,so amyloid-βpeptide and its role in Alzheimer’s disease need to be studied further.Neural stem cells and neural precursor cells are good tools for the study on neurodegenerative diseases and can provide future therapeutic applications in diseases such as Alzheimer’s disease.In this review,we provide an outline of the effects of amyloid-βpeptide,in monomeric and aggregated forms,on the biology of neural stem cells/neural precursor cells,and discuss the controversies.We also describe the possible molecular targets that could be implicated in these effects,especially GSK3β.A better understanding of amyloid-βpeptide(both physiological and pathological),and the signaling pathways involved are essential to advance the field of Alzheimer’s disease.展开更多
There is great interest in the regenerative potential of the neural stem cells and progenitors that populate the subventricular zone（SVZ）. However, a comprehensive understanding of SVZ cell responses to brain injuri...There is great interest in the regenerative potential of the neural stem cells and progenitors that populate the subventricular zone（SVZ）. However, a comprehensive understanding of SVZ cell responses to brain injuries has been hindered by the lack of sensitive approaches to study the cellular composition of this niche. Here we review progress being made in deciphering the cells of the SVZ gleaned from the use of a recently designed flow cytometry panel that allows SVZ cells to be parsed into multiple subsets of progenitors as well as putative stem cells. We review how this approach has begun to unmask both the heterogeneity of SVZ cells as well as the dynamic shifts in cell populations with neonatal and pediatric brain injuries. We also discuss how flow cytometric analyses also have begun to reveal how specific cytokines, such as Leukemia inhibitory factor are coordinating SVZ responses to injury.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
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
基金supported by the Ministry of Science and Technology of China(STI2030-2021ZD0202300)the National Natural Science Foundation of China(32070971,32100768,32200776,and 32200792)the Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)。
文摘Human’s robust cognitive abilities,including creativity and language,are made possible,at least in large part,by evolutionary changes made to the cerebral cortex.This paper reviews the biology and evolution of mammalian cortical radial glial cells(primary neural stem cells)and introduces the concept that a genetically step wise process,based on a core molecular pathway already in use,is the evolutionary process that has molded cortical neurogenesis.The core mechanism,which has been identified in our recent studies,is the extracellular signal-regulated kinase(ERK)-bone morphogenic protein 7(BMP7)-GLI3 repressor form(GLI3R)-sonic hedgehog(SHH)positive feedback loop.Additionally,I propose that the molecular basis for cortical evolutionary dwarfism,exemplified by the lissencephalic mouse which originated from a larger gyrencephalic ancestor,is an increase in SHH signaling in radial glia,that antagonizes ERK-BMP7 signaling.Finally,I propose that:(1)SHH signaling is not a key regulator of primate cortical expansion and folding;(2)human cortical radial glial cells do not generate neocortical interneurons;(3)human-specific genes may not be essential for most cortical expansion.I hope this review assists colleagues in the field,guiding research to address gaps in our understanding of cortical development and evolution.
基金This work was supported by the grant of National Natural Science Foundation of China （No. 30470598）.
文摘Objective To investigate the cell proliferation and differentiation in the developing brain of mouse. Methods C57/BL6 mice were divided into 3 groups at random. Bromodeoxyuridine （BrdU） was injected into the brains in different development periods once a day for 7 d. The brains were retrieved 4 weeks after the last BrdU injection. Immunohistochemical and immunofluorescent studies were carried out for detecting cell proliferation （BrdU） and cell differentiation （NeuN, APC, lbal, and S 100β）, respectively. Results The number of BrdU labeled cells decreased significantly with the development of the brain. Cell proliferation was prominent in the cortex and striatum. A small portion of BrdU and NeuN double labeled cells could be detected in the cortex at the early stage of development, and in the striatum and CA of the hippocampus in all groups. The majority of BrdU labeled cells were neuroglia, and the number of neuroglia cells decreased dramatically with brain maturation. Neurogenesis is the major cytogenesis in the dentate gyrus. Conclusion These results demonstrated that cell proliferation, differentiation and survival were age and brain region related.
基金the Ministry of Education,Science and Technological Development of the Republic of Serbia(Agreement number 451-03-9/2021-14/200042,to MiS,DSN,MM,DD and MaS)the Serbian Academy of Sciences and Arts(Grant number F24,to MiS(PI),MM,DD and MaS)。
文摘Precise tuning of gene expression,accomplished by regulato ry networks of transcription factors,epigenetic modifiers,and microRNAs,is crucial for the proper neural development and function of the brain cells.The SOX transcription factors are involved in regulating diverse cellular processes during embryonic and adult neurogenesis,such as maintaining the cell stemness,cell prolife ration,cell fate decisions,and terminal diffe rentiation into neurons and glial cells.MicroRNAs represent a class of small non-coding RNAs that play important roles in the regulation of gene expression.Together with other gene regulatory factors,microRNAs regulate different processes during neurogenesis and orchestrate the spatial and temporal expression important for neurodevelopment.The emerging data point to a complex regulatory network between SOX transcription factors and microRNAs that govern distinct cellular activities in the developing and adult brain.Deregulated SOX/mic roRNA interplay in signaling pathways that influence the homeostasis and plasticity in the brain has been revealed in various brain pathologies,including neurodegenerative disorders,traumatic brain injury,and cancer.Therapeutic strategies that target SOX/microRNA interplay have emerged in recent years as a promising tool to target neural tissue regeneration and enhance neuro restoration.N umerous studies have confirmed complex intera ctions between microRNAs and SOX-specific mRNAs regulating key features of glioblastoma.Keeping in mind the crucial roles of SOX genes and microRNAs in neural development,we focus this review on SOX/microRNAs interplay in the brain during development and adulthood in physiological and pathological conditions.Special focus was made on their interplay in brain pathologies to summarize current knowledge and highlight potential future development of molecular therapies.
基金supported by grants from the MICINN-ISCⅢ(PI-10/00291 and MPY1412/09)MINECO(SAF2015-71140-R)Comunidad de Madrid(NEUROSTEMCM consortium,S2010/BMD-2336)(all to IL)
文摘Although amyloid-βpeptide is considered neurotoxic,it may mediate several physiological processes during embryonic development and in the adult brain.The pathological function of amyloid-βpeptide has been extensively studied due to its implication in Alzheimer’s disease,but its physiological function remains poorly understood.Amyloid-βpeptide can be detected in non-aggregated(monomeric)and aggregated(oligomeric and fibrillary)forms.Each form has different cytotoxic and/or physiological properties,so amyloid-βpeptide and its role in Alzheimer’s disease need to be studied further.Neural stem cells and neural precursor cells are good tools for the study on neurodegenerative diseases and can provide future therapeutic applications in diseases such as Alzheimer’s disease.In this review,we provide an outline of the effects of amyloid-βpeptide,in monomeric and aggregated forms,on the biology of neural stem cells/neural precursor cells,and discuss the controversies.We also describe the possible molecular targets that could be implicated in these effects,especially GSK3β.A better understanding of amyloid-βpeptide(both physiological and pathological),and the signaling pathways involved are essential to advance the field of Alzheimer’s disease.
文摘There is great interest in the regenerative potential of the neural stem cells and progenitors that populate the subventricular zone（SVZ）. However, a comprehensive understanding of SVZ cell responses to brain injuries has been hindered by the lack of sensitive approaches to study the cellular composition of this niche. Here we review progress being made in deciphering the cells of the SVZ gleaned from the use of a recently designed flow cytometry panel that allows SVZ cells to be parsed into multiple subsets of progenitors as well as putative stem cells. We review how this approach has begun to unmask both the heterogeneity of SVZ cells as well as the dynamic shifts in cell populations with neonatal and pediatric brain injuries. We also discuss how flow cytometric analyses also have begun to reveal how specific cytokines, such as Leukemia inhibitory factor are coordinating SVZ responses to injury.
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 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.
