Adult onset amyotrophic lateral sclerosis (ALS) arises due to progressive and irreversible functional deficits to the central nervous system, specifically the loss of motor neurons. Sporadic ALS causality is not well ...Adult onset amyotrophic lateral sclerosis (ALS) arises due to progressive and irreversible functional deficits to the central nervous system, specifically the loss of motor neurons. Sporadic ALS causality is not well understood, but is almost certainly of multifactorial origin involving a combination of genetic and environmental factors. The discovery of endemic ALS in the native Chamorro population of Guam during the 1950s and the co-occurrence of Parkinsonism and dementia in some patients led to searches for environmental toxins that could be responsible. In the present paper, we report that an environmental neurotoxin enhances mutant superoxide dismutase (SOD)-induced spinal motor neuron death and pathology and induces motor axon abnormalities. These results cumulatively confirm earlier findings that exposure to an environmental toxin is sufficient to produce the disease phenotype and indicate a role for gene-environment interaction in some forms of the disease.展开更多
Formation and plasticity of neural circuits rely on precise regulation of synaptic growth.At Drosophila neuromuscular junction(NMJ),Bone Morphogenetic Protein(BMP)signaling is critical for many aspects of synapse form...Formation and plasticity of neural circuits rely on precise regulation of synaptic growth.At Drosophila neuromuscular junction(NMJ),Bone Morphogenetic Protein(BMP)signaling is critical for many aspects of synapse formation and function.The evolutionarily conserved retromer complex and its associated GTPase-activating protein TBC1D5 are critical regulators of membrane trafficking and cellular signaling.However,their functions in regulating the formation of NMJ are less understood.Here,we report that TBC1D5 is required for inhibition of synaptic growth,and loss of TBC1D5 leads to abnormal presynaptic terminal development,including excessive satellite boutons and branch formation.Ultrastructure analysis reveals that the size of synaptic vesicles and the density of subsynaptic reticulum are increased in TBC1D5mutant boutons.Disruption of interactions of TBC1D5 with Rab7 and retromer phenocopies the loss of TBC1D5.Unexpectedly,we find that TBC1D5 is functionally linked to Rab6,in addition to Rab7,to regulate synaptic growth.Mechanistically,we show that loss of TBC1D5 leads to upregulated BMP signaling by increasing the protein level of BMP type Ⅱ receptor Wishful Thinking(Wit)at NMJ.Overall,our data establish that TBC1D5 in coordination with retromer constrains synaptic growth by regulating Rab7 activity,which negatively regulates BMP signaling through inhibiting Wit level.展开更多
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
文摘Adult onset amyotrophic lateral sclerosis (ALS) arises due to progressive and irreversible functional deficits to the central nervous system, specifically the loss of motor neurons. Sporadic ALS causality is not well understood, but is almost certainly of multifactorial origin involving a combination of genetic and environmental factors. The discovery of endemic ALS in the native Chamorro population of Guam during the 1950s and the co-occurrence of Parkinsonism and dementia in some patients led to searches for environmental toxins that could be responsible. In the present paper, we report that an environmental neurotoxin enhances mutant superoxide dismutase (SOD)-induced spinal motor neuron death and pathology and induces motor axon abnormalities. These results cumulatively confirm earlier findings that exposure to an environmental toxin is sufficient to produce the disease phenotype and indicate a role for gene-environment interaction in some forms of the disease.
基金supported by research grants from the National Natural Science Foundation of China(31671510 and 31871461 to H.H.31771592 to W.X.)。
文摘Formation and plasticity of neural circuits rely on precise regulation of synaptic growth.At Drosophila neuromuscular junction(NMJ),Bone Morphogenetic Protein(BMP)signaling is critical for many aspects of synapse formation and function.The evolutionarily conserved retromer complex and its associated GTPase-activating protein TBC1D5 are critical regulators of membrane trafficking and cellular signaling.However,their functions in regulating the formation of NMJ are less understood.Here,we report that TBC1D5 is required for inhibition of synaptic growth,and loss of TBC1D5 leads to abnormal presynaptic terminal development,including excessive satellite boutons and branch formation.Ultrastructure analysis reveals that the size of synaptic vesicles and the density of subsynaptic reticulum are increased in TBC1D5mutant boutons.Disruption of interactions of TBC1D5 with Rab7 and retromer phenocopies the loss of TBC1D5.Unexpectedly,we find that TBC1D5 is functionally linked to Rab6,in addition to Rab7,to regulate synaptic growth.Mechanistically,we show that loss of TBC1D5 leads to upregulated BMP signaling by increasing the protein level of BMP type Ⅱ receptor Wishful Thinking(Wit)at NMJ.Overall,our data establish that TBC1D5 in coordination with retromer constrains synaptic growth by regulating Rab7 activity,which negatively regulates BMP signaling through inhibiting Wit level.
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.
