The c-Jun N-terminal kinases （JNKs） are important regulators of a variety of physiological and pathological processes both in the central and in the peripheral nervous systems. JNKs are considered as crucial mediato...The c-Jun N-terminal kinases （JNKs） are important regulators of a variety of physiological and pathological processes both in the central and in the peripheral nervous systems. JNKs are considered as crucial mediators of neuronal cell death in response to stress and injury. However, recent studies have provided substantial evidence that the JNK pathway plays an important role in neuronal migration. Here, we will give a brief introduction of the JNK signaling pathway and put more emphasis on its role in nettronal migration.展开更多
In this review, we discuss the role of microtubule-associated protein 1 B （MAP1B） and its phosphorylation in axonal development and regeneration in the central nervous system. MAP1B exhibits similar functions during...In this review, we discuss the role of microtubule-associated protein 1 B （MAP1B） and its phosphorylation in axonal development and regeneration in the central nervous system. MAP1B exhibits similar functions during axonal development and regeneration. MAP1B and phosphorylated MAPIB in neurons and axons maintain a dynamic balance between cytoskeletal components, and regulate the stability and interaction of microtubules and actin to promote axonal growth, neural connectivity and regeneration in the central nervous system.展开更多
Epilepsy is a common,chronic neurological disorder that has been associated with impaired neurodevelopment and immunity.The chemokine receptor CXCR5 is involved in seizures via an unknown mechanism.Here,we first deter...Epilepsy is a common,chronic neurological disorder that has been associated with impaired neurodevelopment and immunity.The chemokine receptor CXCR5 is involved in seizures via an unknown mechanism.Here,we first determined the expression pattern and distribution of the CXCR5 gene in the mouse brain during different stages of development and the brain tissue of patients with epilepsy.Subsequently,we found that the knockdown of CXCR5 increased the susceptibility of mice to pentylenetetrazol-and kainic acid-induced seizures,whereas CXCR5 overexpression had the opposite effect.CXCR5 knockdown in mouse embryos via viral vector electrotransfer negatively influenced the motility and multipolar-to-bipolar transition of migratory neurons.Using a human-derived induced an in vitro multipotential stem cell neurodevelopmental model,we determined that CXCR5 regulates neuronal migration and polarization by stabilizing the actin cytoskeleton during various stages of neurodevelopment.Electrophysiological experiments demonstrated that the knockdown of CXCR5 induced neuronal hyperexcitability,resulting in an increased number of seizures.Finally,our results suggested that CXCR5 deficiency triggers seizure-related electrical activity through a previously unknown mechanism,namely,the disruption of neuronal polarity.展开更多
Postmitotic neurons in the neocortex migrate to appropriate positions and form layered structures of nascent cortex during brain development. The migration of these neurons requires precise control and coordination of...Postmitotic neurons in the neocortex migrate to appropriate positions and form layered structures of nascent cortex during brain development. The migration of these neurons requires precise control and coordination of a large number of molecules such as axon guidance cues. The Eph-ephrin signaling pathway plays important roles in the development of the nervous system in a wide variety of ways, including cell segregation, axon pathfinding, and neuron migration. However, the role of ephrin-B2/ EphA4 signaling in cortical neuron migration remains elusive. Here we demonstrated that ephrin-B2 and its receptor EphA4 were expressed in complementary and overlapping patterns in the developing neocortex. Deletion of the EphA4 gene in the embryonic cerebral cortex resulted in faster migration of cortical neurons, whereas knockdown or overexpression of ephdn-B2 did not alter the normal process of migration. These results suggest that ephrin-B2 forward signaling through EphA4 is required for the precise control of cortical neuron migration.展开更多
Multiple sclerosis（MS）is a chronic inflammatory disease of the central nervous system（CNS）that affects oligodendrocytes and myelin.Loss of myelin leads to progressive axonal damage and neuronal death resulting in ...Multiple sclerosis（MS）is a chronic inflammatory disease of the central nervous system（CNS）that affects oligodendrocytes and myelin.Loss of myelin leads to progressive axonal damage and neuronal death resulting in neurodenegeration and functional disability.Several inflammatory factors influence the development of this neurological disorder.展开更多
Neurons migrate from their birthplaces to the destinations,and extending axons navigate to their synaptic targets by sensing various extracellular cues in spatiotemporally controlled manners.These evolutionally conser...Neurons migrate from their birthplaces to the destinations,and extending axons navigate to their synaptic targets by sensing various extracellular cues in spatiotemporally controlled manners.These evolutionally conserved guidance cues and their receptors regulate multiple aspects of neural development to establish the highly complex nervous system by mediating both short-and long-range cell-cell communications.Neuronal guidance genes(encoding cues,receptors,or downstream signal transducers)are critical not only for development of the nervous system but also for synaptic maintenance,remodeling,and function in the adult brain.One emerging theme is the combinatorial and complementary functions of relatively limited classes of neuronal guidance genes in multiple processes,including neuronal migration,axonal guidance,synaptogenesis,and circuit formation.Importantly,neuronal guidance genes also regulate cell migration and cell-cell communications outside the nervous system.We are just beginning to understand how cells integrate multiple guidance and adhesion signaling inputs to determine overall cellular/subcellular behavior and how aberrant guidance signaling in various cell types contributes to diverse human diseases,ranging from developmental,neuropsychiatric,and neurodegenerative disorders to cancer metastasis.We review classic studies and recent advances in understanding signaling mechanisms of the guidance genes as well as their roles in human diseases.Furthermore,we discuss the remaining chalienges and therapeutic potentials of modulating neuronal guidance pathways in neural repair.展开更多
Autism spectrum disorder(ASD)is a group of neurodevelopmental disorders that cause severe social,communication,and behavioral problems.Recent studies show that the variants of a histone methyltransferase gene KMT5B ca...Autism spectrum disorder(ASD)is a group of neurodevelopmental disorders that cause severe social,communication,and behavioral problems.Recent studies show that the variants of a histone methyltransferase gene KMT5B cause neurodevelopmental disorders(NDDs),including ASD,and the knockout of Kmt5b in mice is embryonic lethal.However,the detailed genotype-phenotype correlations and functional effects of KMT5B in neurodevelopment are unclear.By targeted sequencing of a large Chinese ASD cohort,analyzing published genome-wide sequencing data,and mining literature,we curated 39 KMT5B variants identified from NDD individuals.A genotype-phenotype correlation analysis for 10 individuals with KMT5B pathogenic variants reveals common symptoms,including ASD,intellectual disability,languages problem,and macrocephaly.In vitro knockdown of the expression of Kmt5b in cultured mouse primary cortical neurons leads to a decrease in neuronal dendritic complexity and an increase in dendritic spine density,which can be rescued by expression of human KMT5B but not that of pathogenic de novo missense mutants.In vivo knockdown of the Kmt5b expression in the mouse embryonic cerebral cortex by in utero electroporation results in decreased proliferation and accelerated migration of neural progenitor cells.Our findings reveal essential roles of histone methyltransferase KMT5B in neuronal development,prenatal neurogenesis,and neuronal migration.展开更多
Establishment of axon and dendrite polarity, migration to a desired location in the developing brain, and establishment of proper synaptic connections are essential processes during neuronal development. The cellular ...Establishment of axon and dendrite polarity, migration to a desired location in the developing brain, and establishment of proper synaptic connections are essential processes during neuronal development. The cellular and molecular mechanisms that govern these processes are under intensive investigation. The function of the centrosome in neuronal development has been examined and discussed in few recent studies that underscore the fundamental role of the centrosome in brain development. Clusters of emerging studies have shown that centrosome positioning tightly regulates neuronal development, leading to the segregation of cell factors, directed neurite differentiation, neuronal migration, and synaptic integration. Furthermore, cilia, that arise from the axoneme, a modified centriole, are emerging as new regulatory modules in neuronal development in conjunction with the centrosome. In this review, we focus on summarizing and discussing recent studies on centrosome positioning during neuronal development and also highlight recent findings on the role of cilia in brain development. We further discuss shared molecular signaling pathways that might regulate both centrosome and cilia associated signaling in neuronal development. Furthermore, molecular determinants such as DISC1 and LKB1 have been recently demonstrated to be crucial regulators of various aspects of neuronal development. Strikingly, these determinants might exert their function, at least in part, via the regulation of centrosome and cilia associated signaling and serve as a link between these two signaling centers. We thus include an overview of these molecular determinants.展开更多
Late prenatal growth,early postnatal growth,and layering of the neocortical neurons(NC-Ns)play determining roles in the development of the cerebral cortex(CC).Here,we systematically explore the interactive role of neu...Late prenatal growth,early postnatal growth,and layering of the neocortical neurons(NC-Ns)play determining roles in the development of the cerebral cortex(CC).Here,we systematically explore the interactive role of neuronal surface receptors(NSRs)on cytoskeleton activation(CA)and the piconewton(pN)force generation(P-FG)and their influence on the proper development,growth,and functioning of neurons using a designed DNA nanomechanical device(DNA-NMD).展开更多
Neurogenesis is the process in which neurons are generated from neural stem/progenitor cells(NSCs/NPCs).It involves the proliferation and neuronal fate specification/differentiation of NSCs,as well as migration,maturat...Neurogenesis is the process in which neurons are generated from neural stem/progenitor cells(NSCs/NPCs).It involves the proliferation and neuronal fate specification/differentiation of NSCs,as well as migration,maturation and functional integration of the neuronal progeny into neuronal network.NSCs exhibit the two essential properties of stem cells:self-renewal and multi-potency.Contrary to previous dogma that neurogenesis happens only during development,it is generally accepted now that neurogenesis can take place throughout life in mammalian brains.This raises a new therapeutic potential of applying stem cell therapy for stroke,neurodegenerative diseases and other diseases.However,the maintenance and differentiation of NSCs/NPCs are tightly controlled by the extremely intricate molecular networks.Uncovering the underlying mechanisms that drive the differentiation,migration and maturation of specific neuronal lineages for use in regenerative medicine is,therefore,crucial for the application of stem cell for clinical therapy as well as for providing insight into the mechanisms of human neurogenesis.Here,we focus on the role of bone morphogenetic protein(BMP)signaling in NSCs during mammalian brain development.展开更多
基金This work was supported in part by the National Natural Sciences Foundation of China (No.30530660)the Chinese Academy of Sciences Knowledge Innovation Program (No.KSCX1-YW-R-62)the National Basic Research of China (No.2006CB504100 and No. 2006CB500701).
文摘The c-Jun N-terminal kinases （JNKs） are important regulators of a variety of physiological and pathological processes both in the central and in the peripheral nervous systems. JNKs are considered as crucial mediators of neuronal cell death in response to stress and injury. However, recent studies have provided substantial evidence that the JNK pathway plays an important role in neuronal migration. Here, we will give a brief introduction of the JNK signaling pathway and put more emphasis on its role in nettronal migration.
基金supported by the National Natural Science Foundation of China(Establishment of corticospinal tract ischemic injury model in goat and axonal guidance of microtubule-associated protein 1B in bone marrow-derived mesenchymal stem cells migration in the spinal cord),No. 30972153
文摘In this review, we discuss the role of microtubule-associated protein 1 B （MAP1B） and its phosphorylation in axonal development and regeneration in the central nervous system. MAP1B exhibits similar functions during axonal development and regeneration. MAP1B and phosphorylated MAPIB in neurons and axons maintain a dynamic balance between cytoskeletal components, and regulate the stability and interaction of microtubules and actin to promote axonal growth, neural connectivity and regeneration in the central nervous system.
基金supported by grants from the Science and Technology Program of Chongqing of China(cstc2018jcyjAX003)the National Natural Science Foundation of China(81901322 and 82271497).
文摘Epilepsy is a common,chronic neurological disorder that has been associated with impaired neurodevelopment and immunity.The chemokine receptor CXCR5 is involved in seizures via an unknown mechanism.Here,we first determined the expression pattern and distribution of the CXCR5 gene in the mouse brain during different stages of development and the brain tissue of patients with epilepsy.Subsequently,we found that the knockdown of CXCR5 increased the susceptibility of mice to pentylenetetrazol-and kainic acid-induced seizures,whereas CXCR5 overexpression had the opposite effect.CXCR5 knockdown in mouse embryos via viral vector electrotransfer negatively influenced the motility and multipolar-to-bipolar transition of migratory neurons.Using a human-derived induced an in vitro multipotential stem cell neurodevelopmental model,we determined that CXCR5 regulates neuronal migration and polarization by stabilizing the actin cytoskeleton during various stages of neurodevelopment.Electrophysiological experiments demonstrated that the knockdown of CXCR5 induced neuronal hyperexcitability,resulting in an increased number of seizures.Finally,our results suggested that CXCR5 deficiency triggers seizure-related electrical activity through a previously unknown mechanism,namely,the disruption of neuronal polarity.
基金supported by grants from the Chinese Academy of Sciencesthe National Basic Research Development Program of China (2011CB504102)the National Natural Science Foundation of China (31123002 and 31321091)
文摘Postmitotic neurons in the neocortex migrate to appropriate positions and form layered structures of nascent cortex during brain development. The migration of these neurons requires precise control and coordination of a large number of molecules such as axon guidance cues. The Eph-ephrin signaling pathway plays important roles in the development of the nervous system in a wide variety of ways, including cell segregation, axon pathfinding, and neuron migration. However, the role of ephrin-B2/ EphA4 signaling in cortical neuron migration remains elusive. Here we demonstrated that ephrin-B2 and its receptor EphA4 were expressed in complementary and overlapping patterns in the developing neocortex. Deletion of the EphA4 gene in the embryonic cerebral cortex resulted in faster migration of cortical neurons, whereas knockdown or overexpression of ephdn-B2 did not alter the normal process of migration. These results suggest that ephrin-B2 forward signaling through EphA4 is required for the precise control of cortical neuron migration.
基金This research on MSC was supported by the German Research Foundation(DFGFOR 1103+1 种基金TP1bSTA 518/4-1)
文摘Multiple sclerosis（MS）is a chronic inflammatory disease of the central nervous system（CNS）that affects oligodendrocytes and myelin.Loss of myelin leads to progressive axonal damage and neuronal death resulting in neurodenegeration and functional disability.Several inflammatory factors influence the development of this neurological disorder.
文摘Neurons migrate from their birthplaces to the destinations,and extending axons navigate to their synaptic targets by sensing various extracellular cues in spatiotemporally controlled manners.These evolutionally conserved guidance cues and their receptors regulate multiple aspects of neural development to establish the highly complex nervous system by mediating both short-and long-range cell-cell communications.Neuronal guidance genes(encoding cues,receptors,or downstream signal transducers)are critical not only for development of the nervous system but also for synaptic maintenance,remodeling,and function in the adult brain.One emerging theme is the combinatorial and complementary functions of relatively limited classes of neuronal guidance genes in multiple processes,including neuronal migration,axonal guidance,synaptogenesis,and circuit formation.Importantly,neuronal guidance genes also regulate cell migration and cell-cell communications outside the nervous system.We are just beginning to understand how cells integrate multiple guidance and adhesion signaling inputs to determine overall cellular/subcellular behavior and how aberrant guidance signaling in various cell types contributes to diverse human diseases,ranging from developmental,neuropsychiatric,and neurodegenerative disorders to cancer metastasis.We review classic studies and recent advances in understanding signaling mechanisms of the guidance genes as well as their roles in human diseases.Furthermore,we discuss the remaining chalienges and therapeutic potentials of modulating neuronal guidance pathways in neural repair.
基金supported by the National Natural Science Foundation of China(81871079,81730036,82130043)the National Brain Science and Brain-like Research of China(2021ZD0201704)+2 种基金the National Key Research and Development Program of China(2021YFA0805200)the Hunan Provincial grands(2021JJ10070,2019SK1015,2019RS2005,2019SK1010,B2019138)the High Performance Computing Center of Central South University。
文摘Autism spectrum disorder(ASD)is a group of neurodevelopmental disorders that cause severe social,communication,and behavioral problems.Recent studies show that the variants of a histone methyltransferase gene KMT5B cause neurodevelopmental disorders(NDDs),including ASD,and the knockout of Kmt5b in mice is embryonic lethal.However,the detailed genotype-phenotype correlations and functional effects of KMT5B in neurodevelopment are unclear.By targeted sequencing of a large Chinese ASD cohort,analyzing published genome-wide sequencing data,and mining literature,we curated 39 KMT5B variants identified from NDD individuals.A genotype-phenotype correlation analysis for 10 individuals with KMT5B pathogenic variants reveals common symptoms,including ASD,intellectual disability,languages problem,and macrocephaly.In vitro knockdown of the expression of Kmt5b in cultured mouse primary cortical neurons leads to a decrease in neuronal dendritic complexity and an increase in dendritic spine density,which can be rescued by expression of human KMT5B but not that of pathogenic de novo missense mutants.In vivo knockdown of the Kmt5b expression in the mouse embryonic cerebral cortex by in utero electroporation results in decreased proliferation and accelerated migration of neural progenitor cells.Our findings reveal essential roles of histone methyltransferase KMT5B in neuronal development,prenatal neurogenesis,and neuronal migration.
文摘Establishment of axon and dendrite polarity, migration to a desired location in the developing brain, and establishment of proper synaptic connections are essential processes during neuronal development. The cellular and molecular mechanisms that govern these processes are under intensive investigation. The function of the centrosome in neuronal development has been examined and discussed in few recent studies that underscore the fundamental role of the centrosome in brain development. Clusters of emerging studies have shown that centrosome positioning tightly regulates neuronal development, leading to the segregation of cell factors, directed neurite differentiation, neuronal migration, and synaptic integration. Furthermore, cilia, that arise from the axoneme, a modified centriole, are emerging as new regulatory modules in neuronal development in conjunction with the centrosome. In this review, we focus on summarizing and discussing recent studies on centrosome positioning during neuronal development and also highlight recent findings on the role of cilia in brain development. We further discuss shared molecular signaling pathways that might regulate both centrosome and cilia associated signaling in neuronal development. Furthermore, molecular determinants such as DISC1 and LKB1 have been recently demonstrated to be crucial regulators of various aspects of neuronal development. Strikingly, these determinants might exert their function, at least in part, via the regulation of centrosome and cilia associated signaling and serve as a link between these two signaling centers. We thus include an overview of these molecular determinants.
基金supported by grants from the National Key R&D Program of China(no.2017YFA0700500)the National Natural Science Foundation of China(no.21635004)the Excellent Research Program of Nanjing University(no.ZYJH004).
文摘Late prenatal growth,early postnatal growth,and layering of the neocortical neurons(NC-Ns)play determining roles in the development of the cerebral cortex(CC).Here,we systematically explore the interactive role of neuronal surface receptors(NSRs)on cytoskeleton activation(CA)and the piconewton(pN)force generation(P-FG)and their influence on the proper development,growth,and functioning of neurons using a designed DNA nanomechanical device(DNA-NMD).
文摘Neurogenesis is the process in which neurons are generated from neural stem/progenitor cells(NSCs/NPCs).It involves the proliferation and neuronal fate specification/differentiation of NSCs,as well as migration,maturation and functional integration of the neuronal progeny into neuronal network.NSCs exhibit the two essential properties of stem cells:self-renewal and multi-potency.Contrary to previous dogma that neurogenesis happens only during development,it is generally accepted now that neurogenesis can take place throughout life in mammalian brains.This raises a new therapeutic potential of applying stem cell therapy for stroke,neurodegenerative diseases and other diseases.However,the maintenance and differentiation of NSCs/NPCs are tightly controlled by the extremely intricate molecular networks.Uncovering the underlying mechanisms that drive the differentiation,migration and maturation of specific neuronal lineages for use in regenerative medicine is,therefore,crucial for the application of stem cell for clinical therapy as well as for providing insight into the mechanisms of human neurogenesis.Here,we focus on the role of bone morphogenetic protein(BMP)signaling in NSCs during mammalian brain development.
