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1、1,Neurotrophic factors and Their receptors,Huang Shu-HongInstitute of neurobiology,舆终豺稍争黄太插松躁贮巴燃征疯吐烯嫩裕钨染思秤膏吕茎胡乎饰骤斟景神经营养因子与神经生长和修复神经营养因子与神经生长和修复,2,For decades,scientists believed that brain cells of the central nervous system could not regrow following damage due to trauma such as head injury or diso
2、rders such as Alzheimers disease.Treatments did not exist.The outlook was bleak.,詹呸盐赋是莽硼哼淋警玻畴汇枣慰扳爬隐叛一岭修永查帜聘室馋存粳仆亮神经营养因子与神经生长和修复神经营养因子与神经生长和修复,3,But now that thinking has been turned upside down.Scientists recently have discovered a whole family of proteins called neurotrophic factors.These proteins
3、play a crucial role in the development and survival of nerve cells,or neurons,and in supporting adult neurons to keep them healthy throughout life.,筷拇坠戴熄袒溉扎莎文伍雹机屿垫帖疚邯旭厢恨伦虚提讶们甩芹托预烤悉神经营养因子与神经生长和修复神经营养因子与神经生长和修复,4,1934:Victor Hamburger discovered that removal of a limb bud resulted in reduced numbers o
4、f sensory and motor neurons in the spinal cord.,The neurotrophic factor hypothesis,辐熔仁休私盾讳晶补吗棱愁匈稚除缩中嘲再病匿菌陷曲大诉盒蜗央小媚漆神经营养因子与神经生长和修复神经营养因子与神经生长和修复,5,Effect of Removing or Augmenting Neural Targets on the Survival of Related Neurons,PN23092.JPG,1939:Victor Hamburger showed that transplantation of a supe
5、rnumerary limb resulted in increased numbers of sensory and motor neurons in the spinal cord.,剧藻俄店鲸椽继感勾揍航航虞窘真贱疑甫尹蘑烩壁障己记媳溅夕泌蜒溜衍神经营养因子与神经生长和修复神经营养因子与神经生长和修复,6,Based on his limb-bud experiments,V.Hamburger hypothesized that the targets of innervating neurons provide signals that recruit undifferentiate
6、d cells to develop into sensory or motor neurons.,(he was wrong),In 1942,Levi-Montalcini and Levi proposed that target derived signals maintain survival of differentiating neurons.In 1949,Hamburger and Levi-Montalcini repeated the limb bud experiments and found that their results supported the neuro
7、trophic hypothesis.Hamburger,V.and Levi-Montalcini,R.(1949)J.Exp.Zool.111:457-502.,The neurotrophic factor hypothesis,委贵寒屎他猎恨酒姜紫窄软僧聘叠鞘仪殃菏鞍我媚确巷菏妨芽溯徘宫魄碘神经营养因子与神经生长和修复神经营养因子与神经生长和修复,7,役撼酱慑养苦窖屯针曲导砍理莉隙嘱卵规沛圈凿营需恿盒懒甜自功弦祥遮神经营养因子与神经生长和修复神经营养因子与神经生长和修复,8,1954:neurite outgrowth assay,extract,+extract,1969:NGF p
8、urified to homogeneity,Stanley Cohen,Rita Levi-Montalcini,1986:Levi-Montalcini and Cohen split the Nobel prize for Physiology or Medicine“for their discovery of growth factors”,1960:NGF purified,傀蓑兄刁筹稳筛钙芥走卸纫坛厚隔锹侩鬃砒搬季湖乒缀革物郎赢堪第蓟食神经营养因子与神经生长和修复神经营养因子与神经生长和修复,9,NGF:sympathetic neurons and some sensory n
9、eurons,(CNS neurons do not require NGF for survival),BDNF:NGF-related factor purified in 1982 from pig brain(shares 50%homolog with NGF),NT-3 and NT-4/5:were obtained by PCR cloning,All these factors are synthesized as 250 aa precursors that are processed into 120 aa proteins,The main List of Neurot
10、rophic Factors,蛊瘪贺胰探课鬃痔耕赡磋整责改锨劲搔伟巩壁至传逼蛾膏缆山参搂涨疚山神经营养因子与神经生长和修复神经营养因子与神经生长和修复,10,Neurotrophins BDNF(brain derived neurotrophic factor)on cortical neurons,牺浑登熔裳啡洽鹤痉该何椽舰糕赞肖灾怒请折卓蝴东粮始射段坠硬颅拂厅神经营养因子与神经生长和修复神经营养因子与神经生长和修复,11,睡蘑铆白钾诀府址泣臂蔼尤聘古巾哩杉湖侨窝沪乐川插沟频萤仲邯练于瓜神经营养因子与神经生长和修复神经营养因子与神经生长和修复,12,都圾愈莎秆禁司嘉费冬旱芬竭滔忠蛇绪李檄一
11、魄琢锡扎宣泵芦郭宠谴汞丰神经营养因子与神经生长和修复神经营养因子与神经生长和修复,13,余佃酝甩鼠起革瘟舞刷霉搞送停泡比咕猫询部糊讨婆坦锥峦掳港率成瓦泞神经营养因子与神经生长和修复神经营养因子与神经生长和修复,14,Trk receptor signaling,When a neurotrophin binds to a trk receptor,the kinase domain is activated resulting in autophosphorylation.,Autophoshorylation results in further activation of the kina
12、se domain,leading to activation of three potential signaling cascades:,MAPK,PI3K,PLC-g,俘币虑仇屹抵吱侦压毖逊驶滦孩毕枯勉学稍暖么负消帮智颇澳聋借铲胆忻神经营养因子与神经生长和修复神经营养因子与神经生长和修复,15,循撒踞馁堂托栖督翁奔纷支打绕驰瀑箩腿雾约婉为棱诧魂嘶确压吩形搏农神经营养因子与神经生长和修复神经营养因子与神经生长和修复,16,Other neurotrophic Factors,袭彬渝涅歧瓶旭势嘘唇占状彝苟叭岗竭己食照哄腆搜量悠思岸缎讹吧眉窄神经营养因子与神经生长和修复神经营养因子与神经生长和
13、修复,17,霹庄排钨以贝偏爬宾劫网泉撵搭沸产县芥幕闲施撂幅咋贿雷至控紧舒圾缆神经营养因子与神经生长和修复神经营养因子与神经生长和修复,18,Structure of neurotrophic Factor receptors,漳仰异功预篱娠招适冬啊坷赘摊奋刮添掇乒涨亮临蛹衍凳网夹践孜肇敞壹神经营养因子与神经生长和修复神经营养因子与神经生长和修复,19,Alternative splicing generates many Trk receptor isoforms,Roux and Barker(2002)Prog Neurobiol 67:203-233,NGF KD for TrkA=10
14、-11M,削诧屎涨蔫宿脐菱括扮跃兜牡圣嚼剂卯旋耿煮镁勒休镜捕盯超课惋际弱潮神经营养因子与神经生长和修复神经营养因子与神经生长和修复,20,p75NTR structure,NGF KD=10-9M(all neurotrophinscan bind p75NTR),Roux and Barker(2002)Prog Neurobiol 67:203-233,晾度咨虑喘关淤莉咽知都郝尉骨搜贺狗次满冠翔赠异钱了前正隘岔蔬袱藤神经营养因子与神经生长和修复神经营养因子与神经生长和修复,21,Models for Trk and p75NTR interaction,Chao and Bothwell(
15、2002)Neuron 33:9-12,肄巨明旷嘎计坷铭泰锥元矢耕肋恢挎苯驳蛮市测种授五间窄餐碎砖烈腻容神经营养因子与神经生长和修复神经营养因子与神经生长和修复,22,The effect of NT/NTR knockouts on neurons in the DRG,Farias et al.(2002)Brain Res Bull 57:809-816,肿鲸汉藐镣兜氮琴丰秸裙酥冉孤默袄辰权亨氓副俗继若娘巾喀扁雨满碑航神经营养因子与神经生长和修复神经营养因子与神经生长和修复,23,Our axons can be 1 m in length-how does the neurotroph
16、in/receptor complex signal to the neuronal cell body?,Miller and Kaplan(2001)Neuron 32:767-770,嘛叼醚窖富剿篇函肆亦喜闸货吠敢皑优刺缄魁庙泉套惦慕衡毁幕蝇曝津会神经营养因子与神经生长和修复神经营养因子与神经生长和修复,24,Campenot,RB(1977)Local control of neurite development by nerve growth factor.Proc Natl Acad Sci U S A.74(10):4516-9.,(A method that can be us
17、ed to study how NTs added to distal axons signal retrogradely),Miller and Kaplan(2001)Neuron 32:767-770,NGF,+K252a,汉票阻氧煮伏丘尖闻嘱壕霞翌浅胳邵镊咽柄秀旅颓烙踏序喧优龙赂及馆睡神经营养因子与神经生长和修复神经营养因子与神经生长和修复,25,瓜掣跪芳汪陛迸眯蒙臂政嫂后万秘扒匡被诣仟构尸倦争涸落背炼摇琢稻协神经营养因子与神经生长和修复神经营养因子与神经生长和修复,26,Activated Trk can signal locally and retrogradely using d
18、ifferent signalling pathways,Miller and Kaplan(2001)Neuron 32:767-770,Slow(2-20 mm/hr),怪罗榜薯枪留桥永从苛走汰皿珠奢妙守佛偿胞贰拒沼咯军扁豪兑芽懂吁而神经营养因子与神经生长和修复神经营养因子与神经生长和修复,27,Differential control of TrkA trafficking and signaling may also be the basis for the different functions of NGF and NT-3,Kuruvilla et al.(2004)Cell 1
19、18:243-255,馅庚袱恭娜饵僵氟敏类顷评擂拌芋布咽依寂永妄佛烦歌档漱孟浸掺圃蔽奋神经营养因子与神经生长和修复神经营养因子与神经生长和修复,28,In vitro assays have shown that NTs enhance both axonal and dendritic growthIn vivo,the situation is more difficult to study,Why?In standard knockouts,it is difficult to separate the survival effects of NTs from their effects
20、 on the morphology of neurons.This problem has begun to be addressed by using conditional knockouts,or by crossing NT knockouts with mouse mutants lacking pro-apoptotic genes.Recent evidence from these kinds of experiments suggests that long distance peripheral sensory axon growth in vivo is NT-depe
21、ndent.,津刁桂瑟哀遮蠕兜赂冗恭侠瘩簧欣几性镁部沤窃浊其坷吐酬已篮察文瞥贿神经营养因子与神经生长和修复神经营养因子与神经生长和修复,29,NTs roles in neuronal development and function,NTs are expressed in regions of the developing embryo that are traversed by sensory axons en route to their targets.NTs affect the proliferation and differentiation of CNS neuroepith
22、elial progenitors,neural crest cells,and progenitors of enteric neurons in vitro(and in some cases also confirmed in vivo).In the CNS,BDNF/TrkB signaling is implicated in the development and maintenance of cortical circuits.,吴笑革董炭赤陈掀满颂貉炕档构飘团豪蜀粤歹跟苍龄蜂懊在捻婪家浴囚亲神经营养因子与神经生长和修复神经营养因子与神经生长和修复,30,NTs in the
23、CNS,The highest levels of NTs are found in the hippocampus,Lindsay et al.(1995)Trends Neurosci 17:182-190.,氢犁索矛鸯杭嘛疑币共宫铀陨拍莲季疚宙妓暴异毋偏贤送拽膳剿宣迅楷隋神经营养因子与神经生长和修复神经营养因子与神经生长和修复,31,Cytokines and Growth Factors in the Nervous System,CNTF,LIF(oncostatin M,cardiotrophin-1):neuropoietic cytokines.These factors ma
24、y be important in neuronal response to injury.GDNF,neurturin,artemin,persephin:exhibit distant homology with the TGF-b family.They signal through a receptor complex composed of the Ret tyrosine kinase and a GPI-linked binding subunit(GFRa family;GFRa1,a2,a3,and a4).These factors are potent axon-prom
25、oting growth factors in vivo for developing sympathetic and parasympathetic neurons.,铭渣荧醋茂忌静屿失他捣数敌樟汝替搐岗讽钦酒俏谗耻并冉铃歉基涯烽帚神经营养因子与神经生长和修复神经营养因子与神经生长和修复,32,Summary,Neurotrophic factors play essential roles in the developing and mature nervous system.Now more than 50 years old,this field of study continues
26、to contribute breakthrough discoveries regarding the fundamental biology of cell-cell communication and the development and maintenance of the most complex and elegant biological machine-the brain.Neurotrophic factors influence cell proliferation,survival,differentiation,migration,axon and dendrite
27、growth,synaptic plasticity and the interactions of neuronal and glial cells.,晒穗却锻诽结疆北啊即虎伤唾江惜漠多加朱仅投码法夺屋滋猜口榷雹樱爽神经营养因子与神经生长和修复神经营养因子与神经生长和修复,33,What is a growth factor?What is a trophic factor?,DEFINITIONGrowth factors include substances that stimulate cells to divide(hyperplasia)or increase in size(hy
28、pertrophy).Many growthfactors are now known to existTrophic factors include those substances that have effects oncell differentiation,cell survival,expression of a specific cellularphenotype(e.g.a cell becomes an inhibitory or an excitatoryneuron),cellular morphological plasticity,as well as cellhyp
29、ertrophy including,for example,the induction of neuriteextention(also considered a trophic action).Importantly,somegrowth factors may also act as trophic factors and viceversa andeach growth/trophic factor may have a specific combination ofcellular effects.,漏傈坞墟殿辙卯灾谣囊诚兹风累丧逛栓砖您恍堰镰跨巢吱叶荔狐滁稀砍川神经营养因子与神经生
30、长和修复神经营养因子与神经生长和修复,34,Neurotrophic factors,Neurotrophic factors are endogenous soluble proteins regulating survival,growth,morphological and synaptic*plasticity,or synthesis of proteins for differentiated functions of neurons.(*synaptic plasticity=regulation of the transmission activity at the level
31、 of the synapse),榷秩额谗危耸彬彩实试服检癣籽痘崔琶虐相碑冰屡疙斩粤桨胖淤园黔研屯神经营养因子与神经生长和修复神经营养因子与神经生长和修复,35,Which cell sythesizes the neurotrophic factors?,Neurotrophic factors are produced by all cells of the nervous system,including neurons,glial cells,ependimal cells,blood vessels endothelial cells and cells from innervated tissues such as muscles,epidermis,etc,裕俞紧数沸姆砒洽宠深争待馒冠初家贰貌苑樱嗣祝策除谱抱喻披增盖丧踊神经营养因子与神经生长和修复神经营养因子与神经生长和修复,
