Drosophila neurexin(DNRX) plays a critical role in proper architecture development and synaptic function in vivo. However, the temporal and spatial expression pattern of DNRX still remains unclear. For this study, we ...Drosophila neurexin(DNRX) plays a critical role in proper architecture development and synaptic function in vivo. However, the temporal and spatial expression pattern of DNRX still remains unclear. For this study, we generated a novel Drosophila transgenic strain termed the DNRX-Gal4 transgenic line, with characteristic features in agreement with the endogenous DNRX expression pattern. DNRX expression was examined by driving the expression of a GFP reporter(nuclear-localized and membrane-localized GFP) using the DNRX-Gal4 promoter. We found that DNRX was expressed preferentially in central and motor neurons in embryos, larvae and adults, but not in glial cells. DNRX was expressed in pre- and post-synaptic areas in third instar larvae neuromuscular junctions(NMJs). Reporter expression was also observed in the salivary glands, guts, wings and legs of adult flies. In the adult brain, reporter expression was observed throughout several brain regions, including the mushroom body(MBs), antennal lobe(AL) and optic lobe neurons, which is consistent with endogenous DNRX expression via antibody staining. Interestingly, DNRX was also expressed in clock neurons. Meanwhile, we found that DNRX expression in the MBs was required for olfactory learning and memory.展开更多
Carboxylesterases are enzymes widely distributed within living organisms. In insects, they have been mainly involved in dietary metabolism and detoxification function. Interestingly, several members of this family cal...Carboxylesterases are enzymes widely distributed within living organisms. In insects, they have been mainly involved in dietary metabolism and detoxification function. Interestingly, several members of this family called carboxylesterase-like ad- hesion molecules （CLAMs） have lost their catalytic properties and are mainly involved in neuro/developmental functions. CLAMs include gliotactins, neurotactins, glutactins, and neuroligins. The latter have for binding partner the neurexin. In insects, the function of these proteins has been mainly studied in Drosophila central nervous system or neuro- muscular junction. Some studies suggested a role of neuroligins and neurexin in sensory processing but CLAM expression within sensory systems has not been investigated. Here, we reported the identification of 5 putative CLAMs expressed in the olfactory system of the model pest insect Spodoptera littoralis. One neuroligin, Slnlg4-yll and its putative binding partner neurexin Slnrxl were the most expressed in the antennae and were surprisingly associated with olfactory sensilla. In addition, both transcripts were upregulated in male antennae after mating, known to modulate the sensitivity of the peripheral olfactory system in S. littoralis, suggesting that these molecules could be involved in sensory plasticity.展开更多
Neurexins （NRXNs） have been linked to neurodevelopmental and neuropsychiatric disorders and have become attractive drug targets. They are transmembrane neuronal adhesion molecules and play important roles in the for...Neurexins （NRXNs） have been linked to neurodevelopmental and neuropsychiatric disorders and have become attractive drug targets. They are transmembrane neuronal adhesion molecules and play important roles in the formation and differentiation of synapses and synaptic activity. Many postsynaptic binding partners of NRXNs have been identified. The interactions between NRXNs and postsynaptic binding partners can be regulated by alternative splicing, synaptic activity, and RNA binding proteins. The postsynaptic interactive partners may compete with each other for NRXN binding. The expression of NRXNs can also be regulated transcriptionally and post-transcriptionally. Genetic polymorphism may affect the function and expression of NRXNs. In this review, we will summarize the recent advance in these areas. Understanding the biology of neurexin signaling is essential for developing neurexin-based drugs.展开更多
Gamma-aminobutyric acid(GABA)is the major inhibitory neurotransmitter in the brain.As one of several types of endogenous receptors,GABA_(A)receptors have been shown to be essential in most,if not all,aspects of brain ...Gamma-aminobutyric acid(GABA)is the major inhibitory neurotransmitter in the brain.As one of several types of endogenous receptors,GABA_(A)receptors have been shown to be essential in most,if not all,aspects of brain functioning,including neural development and information processing.Mutations in genes encoding GABA_(A)receptors and alterations in the function of GABA_(A)receptors are associated with many neurologic diseases,and GABA_(A)receptors have been clinically targeted by many drugs,such as benzodiazepines and general anesthetics.Extensive studies have revealed a number of intracellular chaperons/interactions for GABA_(A)receptors,providing a protein-protein network in regulating the trafficking and location of GABA_(A)receptors in the brain.Recently,neurexins and neuroligins,two families of transmembrane proteins present at neurological synapses,are implicated as new partners to GABA_(A)receptors.These works shed new light on the synaptic regulation of GABA_(A)receptor activity.Here,we summarized the proteins that were implicated in the function of GABA_(A)receptors,including neurexins and neuroligins.展开更多
The slit diaphragm bridging the neighboring foot pro-cesses functions as a fnal barrier of glomerular capil-lary wall for preventing the leak of plasma proteins into primary urine. It is now accepted that the dysfunct...The slit diaphragm bridging the neighboring foot pro-cesses functions as a fnal barrier of glomerular capil-lary wall for preventing the leak of plasma proteins into primary urine. It is now accepted that the dysfunction of the sit diaphragm contributes to the development of proteinuria in several glomerular diseases. Neph-rin, a gene product of NPHS1, a gene for a congenital nephrotic syndrome of Finnish type, constitutes an ex-tracellular domain of the slit diaphragm. Podocin was identified as a gene product of NPHS2 , a gene for a familial steroid-resistant nephrotic syndrome of French. Podocin binds the cytoplasmic domain of nephrin. After then, CD2 associated protein, NEPH1 and transient re-ceptor potential-6 were also found as crucial molecules of the slit diaphragm. In order to explore other novel molecules contributing to the development of protein-uria, we performed a subtraction hybridization assay with a normal rat glomerular RNA and a glomerular RNA of rats with a puromycin aminonucleoside ne-phropathy, a mimic of a human minimal change type nephrotic syndrome. Then we have found that synaptic vesicle protein 2B, ephrin-B1 and neurexin were already downregulated at the early stage of puromycin aminonucleoside nephropathy, and that these molecules were localized close to nephrin. It is conceivable that these molecules are the slit diaphragm associated molecules, which participate in the regulation of the barrier func-tion. These molecules could be targets to establish a novel therapy for nephrotic syndrome.展开更多
目的探讨视黄酸受体α(retinoic acid receptorα,RARα)信号变化通过调控视皮质轴突蛋白1(neurexin 1,NRXN1)参与维生素A缺乏(vitamin A deficiency,VAD)大鼠孤独症样行为的机制。方法构建孕期开始的维生素A正常(vitamin A normal,VAN)...目的探讨视黄酸受体α(retinoic acid receptorα,RARα)信号变化通过调控视皮质轴突蛋白1(neurexin 1,NRXN1)参与维生素A缺乏(vitamin A deficiency,VAD)大鼠孤独症样行为的机制。方法构建孕期开始的维生素A正常(vitamin A normal,VAN)和VAD母鼠模型,并在生后早期对部分VAD母鼠和仔鼠给予维生素A补充(vitamin A supplement,VAS)。各组仔鼠(n=20)于6周龄进行行为学检测,利用三箱和旷场实验检测各组仔鼠社交行为和重复刻板行为;采用高效液相色谱法检测各组仔鼠血清视黄醇水平;采用电生理实验检测各组仔鼠视皮质的长时程增强(long-term potentiation,LTP)水平;采用实时荧光定量PCR法和Western blot法检测RARα、NRXN1和N-甲基-D-天冬氨酸受体1(N-methyl-D-aspartate receptor subunit 1,NMDAR1)的表达水平;采用染色质免疫共沉淀技术检测RARα转录因子在NRXN1基因启动子区的富集量。结果VAD组仔鼠出现社会交往障碍、重复刻板等孤独症样行为表现,生后开始的VAS可改善仔鼠大部分行为缺陷。VAD组仔鼠血清视黄醇水平明显低于VAN组和VAS组(P<0.05)。VAD组仔鼠视皮质NMDAR1、RARα和NRXN1的mRNA和蛋白表达水平及LTP水平均较VAN组和VAS组显著降低(P<0.05)。VAD组仔鼠视皮质中RARα转录因子在NRXN1基因启动子区的富集量较VAN组和VAS组显著下降(P<0.05)。结论RARα通过调控NRXN1影响VAD大鼠视皮质突触可塑性,从而参与VAD大鼠孤独症样行为的形成。[中国当代儿科杂志,2022,24(8):928-935]展开更多
As a copper(Cu)transport ATPase,ATP7A plays an important role in maintaining Cu homeostasis in the body,but the developmental and physiological roles of atp7a in zebrafish embryogenesis are rarely studied.In this stud...As a copper(Cu)transport ATPase,ATP7A plays an important role in maintaining Cu homeostasis in the body,but the developmental and physiological roles of atp7a in zebrafish embryogenesis are rarely studied.In this study,normal morphological phenotypes of atp7a^(−/−)homozygous zebrafish were observed at both embryonic and adult stages,however,atp7a^(−/−)larvae exhibited delayed touch response and obvious transcriptome changes.Compared with the WT(wild type),differentially expressed genes(DEGs)in atp7a^(−/−)larvae showed the enrichment in gene ontology(GO)terms related to several processes including ATPase activity,oxidoreductase activity,active transmembrane transporter activity,ion binding,and the citrate cycle.Furthermore,decreases in both ATP content and Na+/K+-ATPase activity in atp7a^(−/−)embryos and larvae were unveiled.57 overlapping DEGs were found both in WT stressed with Cu and in WT mutated with atp7a,and GO term analysis indicated the enrichment in the genes related to neurexin family protein binding and neuronal cell-cell adhesion.Moreover,42 overlapping DEGs in Cu stressed WT and Cu stressed atp7a^(−/−)were identified.GO term analysis showed an enrichment in the genes related to heme binding,implying that Cu was independent of the integral function of atp7a to affect heme binding.In addition,genes involved in the negative regulation of angiogenesis were down-regulated in atp7a^(−/−)mutants with and without Cu stress,which failed to occur in WT,implying that the integral function of atp7a is required for maintaining the normal expression of angiogenesis genes.The integrative data in this study demonstrated that atp7a is required for ion transport and angiogenesis,and for Cu-induced neurexin family protein binding defects,rather than for Cu-induced heme binding defects,during zebrafish embryogenesis.These findings provide possible clues for human diseases with ATP7A dysfunction and imbalanced Cu homeostasis.展开更多
Synapse is a highly specialized inter-cellular structure between neurons or between a neuron and its target cell that mediates cell-cell communications. Ample results indicate that synaptic adhesion molecules are crit...Synapse is a highly specialized inter-cellular structure between neurons or between a neuron and its target cell that mediates cell-cell communications. Ample results indicate that synaptic adhesion molecules are critically important in modulating the complexity and specificity of the synapse. And disruption of adhesive properties of synapses may lead to neurodevelopmental or neurodegenerative diseases. In this review, we will use the Drosophila NMJ as a model system for glutamatergic synapses to discuss the structure and function of homophilic and heterophilic synaptic adhesion molecules with special focus on recent findings in neurexins and neuroligins in Drosophila.展开更多
基金supported by the National Natural Science Founda-tion of China(3117104131000486)the National Basic Research Program of China(2012CB517903)
文摘Drosophila neurexin(DNRX) plays a critical role in proper architecture development and synaptic function in vivo. However, the temporal and spatial expression pattern of DNRX still remains unclear. For this study, we generated a novel Drosophila transgenic strain termed the DNRX-Gal4 transgenic line, with characteristic features in agreement with the endogenous DNRX expression pattern. DNRX expression was examined by driving the expression of a GFP reporter(nuclear-localized and membrane-localized GFP) using the DNRX-Gal4 promoter. We found that DNRX was expressed preferentially in central and motor neurons in embryos, larvae and adults, but not in glial cells. DNRX was expressed in pre- and post-synaptic areas in third instar larvae neuromuscular junctions(NMJs). Reporter expression was also observed in the salivary glands, guts, wings and legs of adult flies. In the adult brain, reporter expression was observed throughout several brain regions, including the mushroom body(MBs), antennal lobe(AL) and optic lobe neurons, which is consistent with endogenous DNRX expression via antibody staining. Interestingly, DNRX was also expressed in clock neurons. Meanwhile, we found that DNRX expression in the MBs was required for olfactory learning and memory.
文摘Carboxylesterases are enzymes widely distributed within living organisms. In insects, they have been mainly involved in dietary metabolism and detoxification function. Interestingly, several members of this family called carboxylesterase-like ad- hesion molecules （CLAMs） have lost their catalytic properties and are mainly involved in neuro/developmental functions. CLAMs include gliotactins, neurotactins, glutactins, and neuroligins. The latter have for binding partner the neurexin. In insects, the function of these proteins has been mainly studied in Drosophila central nervous system or neuro- muscular junction. Some studies suggested a role of neuroligins and neurexin in sensory processing but CLAM expression within sensory systems has not been investigated. Here, we reported the identification of 5 putative CLAMs expressed in the olfactory system of the model pest insect Spodoptera littoralis. One neuroligin, Slnlg4-yll and its putative binding partner neurexin Slnrxl were the most expressed in the antennae and were surprisingly associated with olfactory sensilla. In addition, both transcripts were upregulated in male antennae after mating, known to modulate the sensitivity of the peripheral olfactory system in S. littoralis, suggesting that these molecules could be involved in sensory plasticity.
基金The work is funded by Science Foundation Ireland Investigator＇s award （13/IA/1787） and NUI Galway RSU002.
文摘Neurexins （NRXNs） have been linked to neurodevelopmental and neuropsychiatric disorders and have become attractive drug targets. They are transmembrane neuronal adhesion molecules and play important roles in the formation and differentiation of synapses and synaptic activity. Many postsynaptic binding partners of NRXNs have been identified. The interactions between NRXNs and postsynaptic binding partners can be regulated by alternative splicing, synaptic activity, and RNA binding proteins. The postsynaptic interactive partners may compete with each other for NRXN binding. The expression of NRXNs can also be regulated transcriptionally and post-transcriptionally. Genetic polymorphism may affect the function and expression of NRXNs. In this review, we will summarize the recent advance in these areas. Understanding the biology of neurexin signaling is essential for developing neurexin-based drugs.
基金supported by the National Basic Research Program of China(973 program No.2011CB809102 to C.Z.)“985”Research Foundation of Peking University(to C.Z.).
文摘Gamma-aminobutyric acid(GABA)is the major inhibitory neurotransmitter in the brain.As one of several types of endogenous receptors,GABA_(A)receptors have been shown to be essential in most,if not all,aspects of brain functioning,including neural development and information processing.Mutations in genes encoding GABA_(A)receptors and alterations in the function of GABA_(A)receptors are associated with many neurologic diseases,and GABA_(A)receptors have been clinically targeted by many drugs,such as benzodiazepines and general anesthetics.Extensive studies have revealed a number of intracellular chaperons/interactions for GABA_(A)receptors,providing a protein-protein network in regulating the trafficking and location of GABA_(A)receptors in the brain.Recently,neurexins and neuroligins,two families of transmembrane proteins present at neurological synapses,are implicated as new partners to GABA_(A)receptors.These works shed new light on the synaptic regulation of GABA_(A)receptor activity.Here,we summarized the proteins that were implicated in the function of GABA_(A)receptors,including neurexins and neuroligins.
文摘The slit diaphragm bridging the neighboring foot pro-cesses functions as a fnal barrier of glomerular capil-lary wall for preventing the leak of plasma proteins into primary urine. It is now accepted that the dysfunction of the sit diaphragm contributes to the development of proteinuria in several glomerular diseases. Neph-rin, a gene product of NPHS1, a gene for a congenital nephrotic syndrome of Finnish type, constitutes an ex-tracellular domain of the slit diaphragm. Podocin was identified as a gene product of NPHS2 , a gene for a familial steroid-resistant nephrotic syndrome of French. Podocin binds the cytoplasmic domain of nephrin. After then, CD2 associated protein, NEPH1 and transient re-ceptor potential-6 were also found as crucial molecules of the slit diaphragm. In order to explore other novel molecules contributing to the development of protein-uria, we performed a subtraction hybridization assay with a normal rat glomerular RNA and a glomerular RNA of rats with a puromycin aminonucleoside ne-phropathy, a mimic of a human minimal change type nephrotic syndrome. Then we have found that synaptic vesicle protein 2B, ephrin-B1 and neurexin were already downregulated at the early stage of puromycin aminonucleoside nephropathy, and that these molecules were localized close to nephrin. It is conceivable that these molecules are the slit diaphragm associated molecules, which participate in the regulation of the barrier func-tion. These molecules could be targets to establish a novel therapy for nephrotic syndrome.
文摘目的探讨视黄酸受体α(retinoic acid receptorα,RARα)信号变化通过调控视皮质轴突蛋白1(neurexin 1,NRXN1)参与维生素A缺乏(vitamin A deficiency,VAD)大鼠孤独症样行为的机制。方法构建孕期开始的维生素A正常(vitamin A normal,VAN)和VAD母鼠模型,并在生后早期对部分VAD母鼠和仔鼠给予维生素A补充(vitamin A supplement,VAS)。各组仔鼠(n=20)于6周龄进行行为学检测,利用三箱和旷场实验检测各组仔鼠社交行为和重复刻板行为;采用高效液相色谱法检测各组仔鼠血清视黄醇水平;采用电生理实验检测各组仔鼠视皮质的长时程增强(long-term potentiation,LTP)水平;采用实时荧光定量PCR法和Western blot法检测RARα、NRXN1和N-甲基-D-天冬氨酸受体1(N-methyl-D-aspartate receptor subunit 1,NMDAR1)的表达水平;采用染色质免疫共沉淀技术检测RARα转录因子在NRXN1基因启动子区的富集量。结果VAD组仔鼠出现社会交往障碍、重复刻板等孤独症样行为表现,生后开始的VAS可改善仔鼠大部分行为缺陷。VAD组仔鼠血清视黄醇水平明显低于VAN组和VAS组(P<0.05)。VAD组仔鼠视皮质NMDAR1、RARα和NRXN1的mRNA和蛋白表达水平及LTP水平均较VAN组和VAS组显著降低(P<0.05)。VAD组仔鼠视皮质中RARα转录因子在NRXN1基因启动子区的富集量较VAN组和VAS组显著下降(P<0.05)。结论RARα通过调控NRXN1影响VAD大鼠视皮质突触可塑性,从而参与VAD大鼠孤独症样行为的形成。[中国当代儿科杂志,2022,24(8):928-935]
基金This work was supported by the National Key R&D Program of China(2022YFF1000302)by the project of the Knowledge Innovation Program of Wuhan-Basic Research 2022020801010223by the National Natural Science Foundation of China(Program No.32070807 to J-X.L).
文摘As a copper(Cu)transport ATPase,ATP7A plays an important role in maintaining Cu homeostasis in the body,but the developmental and physiological roles of atp7a in zebrafish embryogenesis are rarely studied.In this study,normal morphological phenotypes of atp7a^(−/−)homozygous zebrafish were observed at both embryonic and adult stages,however,atp7a^(−/−)larvae exhibited delayed touch response and obvious transcriptome changes.Compared with the WT(wild type),differentially expressed genes(DEGs)in atp7a^(−/−)larvae showed the enrichment in gene ontology(GO)terms related to several processes including ATPase activity,oxidoreductase activity,active transmembrane transporter activity,ion binding,and the citrate cycle.Furthermore,decreases in both ATP content and Na+/K+-ATPase activity in atp7a^(−/−)embryos and larvae were unveiled.57 overlapping DEGs were found both in WT stressed with Cu and in WT mutated with atp7a,and GO term analysis indicated the enrichment in the genes related to neurexin family protein binding and neuronal cell-cell adhesion.Moreover,42 overlapping DEGs in Cu stressed WT and Cu stressed atp7a^(−/−)were identified.GO term analysis showed an enrichment in the genes related to heme binding,implying that Cu was independent of the integral function of atp7a to affect heme binding.In addition,genes involved in the negative regulation of angiogenesis were down-regulated in atp7a^(−/−)mutants with and without Cu stress,which failed to occur in WT,implying that the integral function of atp7a is required for maintaining the normal expression of angiogenesis genes.The integrative data in this study demonstrated that atp7a is required for ion transport and angiogenesis,and for Cu-induced neurexin family protein binding defects,rather than for Cu-induced heme binding defects,during zebrafish embryogenesis.These findings provide possible clues for human diseases with ATP7A dysfunction and imbalanced Cu homeostasis.
基金supported by the National Natural Science Foundation of China (Grant Nos. 31171041 and 31000486)National Basic Research Program of China (Grant No. 2012CB517903)
文摘Synapse is a highly specialized inter-cellular structure between neurons or between a neuron and its target cell that mediates cell-cell communications. Ample results indicate that synaptic adhesion molecules are critically important in modulating the complexity and specificity of the synapse. And disruption of adhesive properties of synapses may lead to neurodevelopmental or neurodegenerative diseases. In this review, we will use the Drosophila NMJ as a model system for glutamatergic synapses to discuss the structure and function of homophilic and heterophilic synaptic adhesion molecules with special focus on recent findings in neurexins and neuroligins in Drosophila.
