慢性脑缺血大鼠海马区Numb表达变化的研究
摘要
研究背景及目的
随着人类社会老龄化的进程,痴呆的发病率也逐年增加。在痴呆人群中血管性痴呆(VD)和阿尔兹海默病(AD)占各类痴呆发病的绝大部分,其中VD发病率略高于AD。给社会和家庭带来了严重的经济和精神负担。近年来认为无论是AD还是VD,均与血管因素有关。慢性脑缺血作为神经系统的一种常见病理状态,是由各种原因导致的长期的脑灌流不足,而导致的脑代谢障碍和功能衰退,是血管性痴呆、Binswanger病、Alzheimer病(AD)等多种疾病发展的一个共同病理过程。脑血流低灌注在痴呆发病机制中的作用日渐成为人们关注热点。为此明确痴呆的发病机制特别是在慢性脑缺血的状态下引发的痴呆的发病机制显得尤为重要。既往对慢性脑缺血导致认知功能的研究多集中在脑代谢、脑血管损害、脑内免疫细胞活动、细胞凋亡、突触结构等方面。
Numb蛋白最初在果蝇周围神经系统的发育中被发现的,因其在果蝇细胞中有决定细胞命运的作用被称为细胞命运决定子,随后在哺乳动物以及人的神经系统也发现了同样的功能,但哺乳动物Numb蛋白的结构和功能较果蝇复杂。在近年的研究中发现Numb作为细胞内吞蛋白在神经发育过程中发挥重要作用。不仅参与调节神经前体细胞的不对称分裂、维持神经祖细胞的自我更新还参与调控神经细胞迁移和神经突生长等。本实验预通过检测慢性脑缺血大鼠认知功能的改变及海马区Numb表达的动态变化初步探讨慢性脑缺血所致的认知功能改变和Numb之间的关系及可能机制。为缺血性脑血管病所引起的认知障碍的研究与治疗提供理论依据。
方法
1.雄性SD大鼠40只,鼠龄大于12个月,随机分为假手术组、缺血8周组、缺血10周组、缺血12周组4组,每组10只。
2.采用永久性双侧颈总动脉结扎制备脑灌注不足模型(2VO模型),假手术组除不接扎双侧颈动脉外余处理与手术组相同。
3.各组在对应时间进行Morris水迷宫试验,检测大鼠的学习和记忆功能。
4.通过免疫组化检测大鼠海马CA1区Numb的表达。
5.通过Western bolt检测大鼠海马的Numb表达
6.数据采集和数据分析。
结果
1.行为学检测结果显示,缺血组大鼠逃避潜伏期较假手术组明显延长,穿越平台次数明显减少,且随着缺血时间的延长,逃避潜伏期进行性延长,穿越平台次数进行性减少,表明2VO术后大鼠学习记忆能力明显受损,且随缺血时间延长进行性加重。
2.免疫组化半定量结果显示,缺血组大鼠海马CA1区Numb表达较假手术组明显减少,并随缺血时间的延长进行性减少。
3.Western bolt结果显示,缺血组大鼠海马CA1区Numb表达较假手术组明显减少,并随缺血时间的延长进行性减少。
结论
2VO术后8周至12周中,随着缺血时间的延长大鼠认知进行性损害、Numb表达进行性下降。Numb表达的进行性下降可能是慢性缺血导致认知功能障碍的重要原因之
Background and objective:
With the population aging in our country, the incidence of the dementia is increasing year by year. Vascular dementia (VD) and alzheimer's disease (AD) accounted for most of dementia, and the incidence of VD is higher than AD. Dementia brought serious economic and mental burden for the whole society and his family. In recent years, both VD and AD have been considered with vascular factors. Chronic cerebral ischemia is a common pathological state of nervous system, which is caused by the long time insufficient of cerebral perfusion. This pathological state as a common pathological process of VD, Binswanger disease and AD, can lead to the disorder of cerebral metabolic and function. It's more and more important to explore the mechanism of dementia which caused by the cerebral hypoperfusion. Many studies have been done for the cognitive impairment caused by chronic cerebral ischemia, such as:cerebral metabolism, cerebrovacular damage, the activity of immune cells, cell apotosis, synaptic structure and so on. Numb was firstly found in the development of the peripheral nervous system in drosophila. Numb can decide the cell fate in drosophila, that's why it was called as cell fate determinant. Then the function of cell fate decision has also been found in mammals and people. The structure and function is more complex in mammals than in drosophila. Numb as an endocytosis protein plays an important role in the nerve development process in recent studies. Numb not only pateicipates in the adjustment of the asymmetric division of neural precursor cell, maintain the neural progenitor cells's self-refreshment, but also participates in the regulation of nerve cell's migration and the neurite growth. In order to investigate the relationship and its possible mechanism of the expression of Numb in the hippocampus and the congnitive function after chronic cerebral ischemic, we will detect the congnitive fuction and the expression of Numb in the hippocampus in aged chronic cerebral ischemic rats to provide the basis theory of the research and treatment for the cognitive impairment caused by ischemic cerebrovascular disease.
Materials and methods:
1.40healthy male SD rats(age more than12months) were divided into four groups at random:sham-operated group, experimental groups of8weeks,10weeks and12weeks.
2. The chronic cerebral ischemia models were produced by permanent occlusion of bilateral common carotid arteries (2VO model), the sham-operated group accept the same operation except occlusion of bilateral common carotid arteries.
3. The performance in Morris water maze of each group at the right time was investigated to explore the learning and memory ability of rats.
4. The expression of Numb in the CA1of hippocampus was measured by immunohistochemical technique.
5. The expression of Numb in the hippocampus was measured by Western blotting.
6. Data collection and data analysis.
Results
1. As compared with the sham-operated rats, the experimental groups showed a significantly increased latency of the rats to find the hidden platform and the times of crossing the platform zone when the plateform was removed had a significantly diminished in Morris water maze task, this would be more obvious when the time of cerebral ischemia was longer. It was indicated that the spatial learning and memory abilities of2VO rats were sharply impaired and with the extension of ischemia time this situation would be more serious.
2. As compared with the sham-operated rats, the expressions of Numb in the CA1of hippocampus of experimental groups which measured by immunohistochemical technique was notebly decreased, and with the extension of ischemia time the expressions of Numb would be less and less.
3. As compared with the sham-operated rats, the expressions of Numb in the hippocampus of experimental groups which measured by Western blotting was notebly decreased, and the expressions of Numb would be less and less when the time of cerebral ischemia was longer.
Conclusion:
1. In the rats8-12weeks after2VO, as the extension of ischemia time, the cognitive function was damaged and the expression of Numb in the hippocampus was declined.
2. The decline expression of Numb after chronic cerebral ischemia may play an important role in cognitive impairment of aged rats.
随着人类社会老龄化的进程,痴呆的发病率也逐年增加。在痴呆人群中血管性痴呆(VD)和阿尔兹海默病(AD)占各类痴呆发病的绝大部分,其中VD发病率略高于AD。给社会和家庭带来了严重的经济和精神负担。近年来认为无论是AD还是VD,均与血管因素有关。慢性脑缺血作为神经系统的一种常见病理状态,是由各种原因导致的长期的脑灌流不足,而导致的脑代谢障碍和功能衰退,是血管性痴呆、Binswanger病、Alzheimer病(AD)等多种疾病发展的一个共同病理过程。脑血流低灌注在痴呆发病机制中的作用日渐成为人们关注热点。为此明确痴呆的发病机制特别是在慢性脑缺血的状态下引发的痴呆的发病机制显得尤为重要。既往对慢性脑缺血导致认知功能的研究多集中在脑代谢、脑血管损害、脑内免疫细胞活动、细胞凋亡、突触结构等方面。
Numb蛋白最初在果蝇周围神经系统的发育中被发现的,因其在果蝇细胞中有决定细胞命运的作用被称为细胞命运决定子,随后在哺乳动物以及人的神经系统也发现了同样的功能,但哺乳动物Numb蛋白的结构和功能较果蝇复杂。在近年的研究中发现Numb作为细胞内吞蛋白在神经发育过程中发挥重要作用。不仅参与调节神经前体细胞的不对称分裂、维持神经祖细胞的自我更新还参与调控神经细胞迁移和神经突生长等。本实验预通过检测慢性脑缺血大鼠认知功能的改变及海马区Numb表达的动态变化初步探讨慢性脑缺血所致的认知功能改变和Numb之间的关系及可能机制。为缺血性脑血管病所引起的认知障碍的研究与治疗提供理论依据。
方法
1.雄性SD大鼠40只,鼠龄大于12个月,随机分为假手术组、缺血8周组、缺血10周组、缺血12周组4组,每组10只。
2.采用永久性双侧颈总动脉结扎制备脑灌注不足模型(2VO模型),假手术组除不接扎双侧颈动脉外余处理与手术组相同。
3.各组在对应时间进行Morris水迷宫试验,检测大鼠的学习和记忆功能。
4.通过免疫组化检测大鼠海马CA1区Numb的表达。
5.通过Western bolt检测大鼠海马的Numb表达
6.数据采集和数据分析。
结果
1.行为学检测结果显示,缺血组大鼠逃避潜伏期较假手术组明显延长,穿越平台次数明显减少,且随着缺血时间的延长,逃避潜伏期进行性延长,穿越平台次数进行性减少,表明2VO术后大鼠学习记忆能力明显受损,且随缺血时间延长进行性加重。
2.免疫组化半定量结果显示,缺血组大鼠海马CA1区Numb表达较假手术组明显减少,并随缺血时间的延长进行性减少。
3.Western bolt结果显示,缺血组大鼠海马CA1区Numb表达较假手术组明显减少,并随缺血时间的延长进行性减少。
结论
2VO术后8周至12周中,随着缺血时间的延长大鼠认知进行性损害、Numb表达进行性下降。Numb表达的进行性下降可能是慢性缺血导致认知功能障碍的重要原因之
Background and objective:
With the population aging in our country, the incidence of the dementia is increasing year by year. Vascular dementia (VD) and alzheimer's disease (AD) accounted for most of dementia, and the incidence of VD is higher than AD. Dementia brought serious economic and mental burden for the whole society and his family. In recent years, both VD and AD have been considered with vascular factors. Chronic cerebral ischemia is a common pathological state of nervous system, which is caused by the long time insufficient of cerebral perfusion. This pathological state as a common pathological process of VD, Binswanger disease and AD, can lead to the disorder of cerebral metabolic and function. It's more and more important to explore the mechanism of dementia which caused by the cerebral hypoperfusion. Many studies have been done for the cognitive impairment caused by chronic cerebral ischemia, such as:cerebral metabolism, cerebrovacular damage, the activity of immune cells, cell apotosis, synaptic structure and so on. Numb was firstly found in the development of the peripheral nervous system in drosophila. Numb can decide the cell fate in drosophila, that's why it was called as cell fate determinant. Then the function of cell fate decision has also been found in mammals and people. The structure and function is more complex in mammals than in drosophila. Numb as an endocytosis protein plays an important role in the nerve development process in recent studies. Numb not only pateicipates in the adjustment of the asymmetric division of neural precursor cell, maintain the neural progenitor cells's self-refreshment, but also participates in the regulation of nerve cell's migration and the neurite growth. In order to investigate the relationship and its possible mechanism of the expression of Numb in the hippocampus and the congnitive function after chronic cerebral ischemic, we will detect the congnitive fuction and the expression of Numb in the hippocampus in aged chronic cerebral ischemic rats to provide the basis theory of the research and treatment for the cognitive impairment caused by ischemic cerebrovascular disease.
Materials and methods:
1.40healthy male SD rats(age more than12months) were divided into four groups at random:sham-operated group, experimental groups of8weeks,10weeks and12weeks.
2. The chronic cerebral ischemia models were produced by permanent occlusion of bilateral common carotid arteries (2VO model), the sham-operated group accept the same operation except occlusion of bilateral common carotid arteries.
3. The performance in Morris water maze of each group at the right time was investigated to explore the learning and memory ability of rats.
4. The expression of Numb in the CA1of hippocampus was measured by immunohistochemical technique.
5. The expression of Numb in the hippocampus was measured by Western blotting.
6. Data collection and data analysis.
Results
1. As compared with the sham-operated rats, the experimental groups showed a significantly increased latency of the rats to find the hidden platform and the times of crossing the platform zone when the plateform was removed had a significantly diminished in Morris water maze task, this would be more obvious when the time of cerebral ischemia was longer. It was indicated that the spatial learning and memory abilities of2VO rats were sharply impaired and with the extension of ischemia time this situation would be more serious.
2. As compared with the sham-operated rats, the expressions of Numb in the CA1of hippocampus of experimental groups which measured by immunohistochemical technique was notebly decreased, and with the extension of ischemia time the expressions of Numb would be less and less.
3. As compared with the sham-operated rats, the expressions of Numb in the hippocampus of experimental groups which measured by Western blotting was notebly decreased, and the expressions of Numb would be less and less when the time of cerebral ischemia was longer.
Conclusion:
1. In the rats8-12weeks after2VO, as the extension of ischemia time, the cognitive function was damaged and the expression of Numb in the hippocampus was declined.
2. The decline expression of Numb after chronic cerebral ischemia may play an important role in cognitive impairment of aged rats.
引文
[1]Jong GID, Farkas E, Plass J,etal. Cerebral hypoperfusion yields capillary damage in hippocampus CA1 that correlates to spatial memory impairment[J].Neurosicence,1999; 91:203-10.
[2]Michael K,Morgan, Lali HS.Sekhon,etal.Defining the role of capillaries in "nornal perfusion pressure breakthrough,"and"occlusive hyperemia"[J].Clin Neurol Neurosurgery, 1997;99:13.
[3]Ni JW,Matsumoto K,Li HB, et al.Neuronal damage and decrease of central acetylcholine level following permanent occlusion of bilateral common carotid arteries in rat[J].Brain Res,1995,673(2):290-6.
[4]Bennett SA,Tenniswood M,Chen JH,etal.Chronic cerebral hypoperfusion elicits neuronal apoptosis and behavioral impairment[J].Neuroreport,1998,9:161-6
[5]Sarti C, Pantoni L, Bartolini L, et al. Cognitive impairment and chronic cerebral hypoperfusion:What can be learned from experimental models[J].Neuro Sci,2002,203-204: 263-6
[6]Li MW,Yi FH,Xi CT.Huperzine A improves cognitive denficits caused by chronic cerebral hypoperfusion in rats[J]. Eur J Pharmacol,2000,398:65-72
[7]Bischormer R,Adjodah D.Long-term expression of heme oxygenase-1 (hsp-32) following focal cerebral infarctions and traumatic brain injury in humans[J].Acta Neuropathologica, 2000,100(04):377-384
[8]Torre DL,Cada JC, Nelson A, etal. Reduced cytochmme oxidase and memory dysfunction after chronic brain ischemia in aged rats[J]. Neurosci Lett,1997,223:165-8
[9]Gehrmann J,Banati RB,Wiessner C.Reactive microglia in cerebral ischemia:an early mediator of tissur damage[J].Neuropathology and Applied Neurobiology,1995,21:277-289.
[10]XiaoZhen Zhao, Wei Wang.ZhongHan Kang etal. structural changes in the hippocampal synapse of rats with vascular dementia [J].Chinese Journal of Clinical Rehabilization, 2003,7(311):4213-15.
[11]Chen Y.Neuronal Synaptic Plasticty,Learning and Memory[J]. Progress in biochemistry and Biophysics [J].2008,35(6):610-619.
[12]Santolini E,Puri C,Salcini AE, etal.Numb is an endocytic protein[J].Cell Biol,2000,151(6): 1345-51.
[13]Wodarz A. Molecular control of cell polarity and asymmetric cell division in Drosophila neuroblasts[J].Curr Opin Cell Biol,2005,17(5):475-81.
[14]Cayouette M,Raff M.Asymmetric segregation of Numb:a mechanism for neural specification from Drosophila to mammals[J].Nat Neurosci,2002,5(12):1265-9.
[15]Karaczyn Aldona,Bani-Yaghoub Mahmud,Tremblay Roger,etal.Two novel human NUMB isoforms provide a potential link between development and cancer[J].Neural Development, 2011,5(1).
[16]De la Torre, J.C. Vascular basis of Alzheimer's pathogenesis[J].Ann. N. Y. Acad.2002. 977,196-215.
[17]Borroni B,Anchisi D,Paghera B.Combined 99mTc-ECD SPECT and neuropsychological studies in MCI for the assessment of conversion to AD[J].Neurobiology of Aging,2006,27: 24-31.
[18]De Jong-GI, Farkas E, Stienstra CM, et al. Cerebral hypoperfusion yields capillary damage in the hippocampal CA1 area that correlates with spatial memory impairment.[J]. Neuroscience,1999,91(1):203-210.
[19]Farkas E,Luiten PG,Bari F,et al.Permanent, bilateral common carotid artery occlusion in the rat:a model for chronic cerebral hypoperfusion-related neurodegenerative diseases.[J].Brain Research Reviews,2007,54(1):162-180
[20]XiaoZhen Zhao, Wei Wang, ZhongHan Kang et al. structural changes in the hippocampal synapse of rats with vascular dementia [J].Chinese Journal of Clinical Rehabilization, 2003,7(311):4213-15.
[21]Dawson D.A., Hallenbeck J.M. Acute focal ischemia-induced alterations in MAP2 immunostaining:description of temporal changes and utilization as a marker for volumetric assessment of acute brain injury[J].Cereb Blood Flow Metab.1996,16,170-174.
[22]Friedrich P, Aszodi A. MAP2:a sensitive cross-linker and adjustable spacer in dendritic architecture[J]. FEBS Lett.1991,295:5-9.
[23]Liu H X, Zhang JJ, Zheng P, et al. Altered expression of MAP-2, GAP-43, and synaptophysin in the hippocampus of rats with chronic cerebral hypoperfusion correlates with cognitive impairment[J]. Brain Res.2005.139,169-177.
[24]刘秀丽.基于GFP的FRET监测树突棘钙动力学[D].华中科技大学,2005.
[25]Cayouette M, Raff M, Asymmetric segregation of Numb:a mechanism for neural specification from Drosophila to mammals[J].Nat Neurosci,2002,5(12):1265-9.
[26]Nishimura T, Fukata Y, Kato K, et al.CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth[J]. Nat Cell Biol,2003,5(9):819-26
[27]Nishimura T,Kaibuchi K.Numb controls integrin endocytosis for directional cell migration with aPKC and PAR-3[J].Dev Cell,2007;13(1):15-28
[28]Kyriazis, GA,Wei, Z,Vandermey, M et al.Numb Endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoform-dependent manner-Implications for Alzheimer disease pathogenesis[J].The Journal of Biological Chemistry,2008,283(37):25492-25502
[29]Thomas S.Ritter B,Verbich D,et al.Intersectin regulates dendritic spine development and somatodendritic endocytosis but not synaptic vesicle recycling in hippocampal neurons[J], Biol Chem,2009,284(18):12410-9.3.
[30]Nishimura T,Yamaguchi T,Tokunaga A,et al.Role of numb in dendritic spine development with a Cdc42 GEF intersectin and EphB2[J]. Mol Biol Cell,2006,17(3):1273-85.3.
[31]Lu CB,Fu W,Xu X et al.Numb-mediated neurite outgrowth is isoform-dependent, and requires activation of voltage-dependent calcium channels.[J].Neuroscience,2009,161(2): 403-412.
[32]Fukata Y,Itoh TJ,Menager C, etal.CRMP-2 binds to tubulin heterodimers to promote microtubule assembly[J].Nat Cell Biol 2002,4(8):583-91.5.
[33]ZhouY,Atkins JB,Rompani SB, etal.The mammalian golgi regulates numb signaling in asymmetric cell division by releasing ACBD3 during mitosis[J].Cell,2007,129(1):163-78.
[34]Chapman G, Liu LN,Sahlgren C，etal.High levels of Notch signaling down-regulate Numb and Numblike[J].Cell Bilo,2006,175(4):535-40.
[35]Bart lett PF, Brook er GJ, Fau x CH, et al. Regu lat ion of neural stem cell dif ferent iat ion in the forebrain[J]. Immunol Cell Biol,1998,76:414～418.
[36]Mc Connell SK. Constructing the cerebral co rtex:neurogenesis and fate determ ination[J]. Neuron,1995,(15):761-768.
[37]Ghysen A,Dambly-Chaudiere C,Jan LY,et al.Cell interactions and gene interactions in peripheral neurogenesis[J].Genes Dev,1993,7:723-733.
[38]张绍梅,王素娥,彭争荣等.脑出血模型大鼠针刺穴位后其血清对脑源性神经干细胞膜相关蛋白Numb表达的影响[J].医学临床研究,2007,24(9)：1464-1467.
[39]Kyriazis GA, Wei Z, Vandermey M, et al. Numb endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoformdependent manner: implications for Alzheimer disease pathogenesis[J]. Biol Chem,2008,283:25492-502.
[40]Koo EH, Squazzo SL. Evidence that production and release of amyloid beta-protein involves the endocytic pathway[J].Biol Chem,1994,269:17386-9.
[41]Chan SL,Pedersen WA,Zhu H.Numb modifies neuronal vulnerability to amyloid beta-peptide in an isoformspecific manner by a mechanism involving altered calcium homeostasis:implications for neuronal death in Alzheimer's disease[J].Neuromoleculdar Mod,2002,1:55-67
[1]Verdi JM, Bashirullah A, Goldhawk DE, et al. Distinct human NUMB isoforms regulate differentiation vs. proliferation in the neuronal lineage[J]. Proc Natl Acad Sci USA, 1999,96:10472-6.
[2]Nie J, McGill MA, Dermer M, etal. LNX functions as a RING type E3 ubiquitin ligase that targets the cell fate determinant Numb for ubiquitin-dependent degradation[J]. EMBO, 2002,21:93-102.
[3]Kyriazis GA, Wei Z, Vandermey M,et al. Numb endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoformdependent manner: implications for Alzheimer disease pathogenesis[J].Biol Chem,2008,283:25492-502.
[4]Karaczyn Aldona,Bani-Yaghoub Mahmud,Tremblay Roger,etal.Two novel human NUMB isoforms provide a potential link between development and cancer[J].Neural Development, 2011,5(1).
[5]Nishimura T, Yamaguchi T, Kato K, etal. PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiaml[J]. Nat Cell Biol,2005,7:270-277.
[6]Ong CT, Cheng HT, Chang LW, etal. Target selectivity of vertebrate notch proteins. Collaboration between discrete domains and CSL-binding site architecture determines activation probability[J]. Biol Chem,2006,281:5106-5119.
[7]Tirnauer JS. A new cytoskeletal connection for APC:linked to actin through IQGAP[J]. Dev Cell,2004,7:778-780.
[8]Chenn A,Mcconnell SK.Cleavage orientation and the asymetric inheritance of Notch 1 immunoreactivity in mammalian neurogenesis[J].Cell,1995,82(4):631-41.
[9]Konno D,Ahioi G,Shitamukai A, etal.Neuroepithelial porgenitors undergo LGN-dependent planar divisions to maintain self-renewability during mammalian neurogenesis[J].Nat Cell Biol 2008,10(1):93-101.
[10]E. Santolini, C. Puri, A.E. Salcini, etal.Numb is an endocytic protein[J]. Cell Biol.2000, 151:1345-1352.
[11]J.A. Knoblich, Mechanisms of asymmetric stem cell division[J].Cell,2008,132:583-597.
[12]Petersen PH,Tang HY,Zou KY,etal.The enigma of the Numb-Notch relationgship during mammalian embryogenesis[J].Dev Neurosci,2006,28(1-2):156-68.
[13]McGill MA, McGlade CJ. Mammalian numb proteins promote notchl receptor ubiquitination and degradation of the notch 1 intracellular domain[J].Biol Chem,2003,278 (25):23196-203.
[14]Chapman G,Liu LN,Sahlgren C,etal.High levels of Notch signaling down-regulate Numb and Numblike[J].Cell Bilo,2006:175(4):535-40.
[15]T. Ito, H.Y. Kwon, B. Zimdahl, etal. Regulation of myeloid leukaemia by the cell-fate determinant Musashi[J], Nature,2010,466:765-768.
[16]C. Zhao, A. Chen, C.H. Jamieson, etal. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia[J], Nature,2009,458:776-779.
[17]C. Dierks, R. Beigi, G.R. Guo, etal. Expansion of Bcr-Ablpositive leukemic stem cells is dependent on Hedgehog pathway activation[J].Cancer Cell,2008,14:238-249.
[18]L. Lanzetti, P.P. Di Fiore, Endocytosis and cancer:an'insider'network with dangerous liaisons[J].Traffic,2008,9:2011-2021.
[19]Singh, J. Settleman, EMT, cancer stem cells and drug resistance:an erging axis of evil in the war on cancer[J].Oncogene,2010,29:4741-4751.
[20]P.B. Gupta, C.L. Chaffer, R.A. Weinberg.Cancer stem cells:mirage or reality[J].Nat.Med. 15 (2009)1010-1012.
[21]Nassar A,Sexton D,Cotsonis G,etal.Survivin expression in breast carcinoma:Correlation with apoptosis and prognosis[J].Appl Immunohistochem Mol Morphol,2008,16(3):221.
[22]Colaluca IN, Tosoni D, Nuciforo P,et al. Numb controls p53 tumour suppressor activity [J]. Nature,2008,451(7174):76-80.
[23]Santolini E,Puri C,Salcini AE,etal.Numb is an endocytic protein[J]. Cell Biol,2000;151(6): 1345-51.
[24]Fukata Y,Itoh TJ,Menager C,Nishimura T,Shiromizu T etal.CRMP-2 binds to tubulin heterodimers to promote microtubule assembly.Nat Cell Biol 2002,4(8):583-91.
[25]Nishimura T, Fukata Y, Kato K, et al. CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth[J]. Nat Cell Biol,2003,5(9):819-26.
[26]XiaoZhen Zhao,Wei Wang,ZhongHan Kang etal. structural changes in the hippocampal synapse of rats with vascular dementia [J].Chinese Journal of Clinical Rehabilization,2003, 7(311):4213-15.
[27]Dendritic morphology of neurons in medial prefrontal cortex and hippocampus in 2VO rats
[28]Sengar, A. S., Wang, W., Bishay, J.etal. The EH and SH3 domain Ese proteins regulate endocytosis by linking to dynamin and Eps15[J], EMBO,1999,18:1159-1171.
[29]Tokumitsu, H., Hatano, N., Inuzuka, H., etal. Phosphorylation of Numb family proteins. Possible involvement of Ca2_/calmodulin-dependent protein kinases.[J]. Biol. Chem. 2005,280:35108-35118.
[30]Govek, E. E., Newey, S. E., and Van Aelst, L.. The role of the Rho GTPases in neuronal development[J]. Genes Dev.2005,19:1-49.
[31]Penzes P, Beeser A, Chernoff J, etal. Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin[J]. Neuron,2003, 37:263-274.
[32]Huang Eric J,Li Huashun,Tang Amy,etal.Targeted deletion of numb and numblike in sensory neurons reveals their essential functions in axon arborization[J]. Genes Dev,2005, 19:138-151.
[33]Pedersen WA, Chan SL, Zhu H,etal. Numb isoforms containing a short PTB domain promote neurotrophic factor-induced differentiation and neurotrophic factor withdrawal-induced death of PC12 Cells[J]. Neurochem,2002,82:976-986.
[34]Ronn LCB.,Dissing S.,Holm A. et al.Increased intracellular calcium is required for neurite outgrowth induced by a synthetic peptide ligand of NCAM[J].FEBS Letters,2002,518(1/3): 60-66
[35]Lu CB,Fu W,Xu X et al.Numb-mediated neurite outgrowth is isoform-dependent, and requires activation of voltage-dependent calcium channels.[J]. Neuroscience,2009,161(2): 403-412.
[36]Kyriazis GA, Wei Z, Vandermey M, et al. Numb endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoformdependent manner: implications for Alzheimer disease pathogenesis[J]. Biol Chem 2008;283:25492-502.
[37]Koo EH, Squazzo SL. Evidence that production and release of amyloid beta-protein involves the endocytic pathway[J]. Biol Chem 1994;269:17386-9.
[38]ZhouY,Atkins JB,Rompani SB, etal.The mammalian golgi regulates numb signaling in asymmetric cell division by releasing ACBD3 during mitosis[J]. Cell 2007;129(1):163-78.
[39]NiggErichA.Cyclin-dependent protein kinases:key regulators of the eukaryotic cell cycle [J].Bioessays,1995,17(6):471-80.
[40]Dho Sascha E,Jacob Sara,Wolting Cheryl D,etal.The mammalian Numb phosphotyrosine-binding domain characterization of binding specificity and identification of a novel PDZ domain-containing numb binding protein,LNX[J].THE JOURNAL OF BIOLOGICAL CHEMISTRY,1998,273(15):9179-9187.
[41]Rice Dennis,Northcutt Grace M,Kurschner Cornelia.The LNX Family Proteins Function as Molecular Scaffolds for Numb Family Proteins [J].Molecular and Cellular Neuroseienee, 2001,18:525-540.
[42]Sollerbrant Kerstin,Raschperger Elisabeth,Mriza Momina,etal.The Coxsackievirus and Adenovirus Receptor(CAR) Forms a Complex with the PDZ Domain-containing Protein Ligand-of-Numb Protein-X(LNX)[J].THE JOURNAL OF BIOLOGICAL CHEMISTRY, 2003,Vol.278,No.9(February 28):7439-7444.
[43]ShuFang, LvShun, QinYan, etal.Functional characterization of human PFTK1 as a cyclin-dependent kinase [J].PNAS,2007,104(22):9248-9253.
[44]Bart lett PF, Brook er GJ, Fau x CH, et al. Regu lat ion of neural stem cell dif ferent iat ion in the f orebrain [J]. Immunol Cell Biol,1998,76:414～418.
[45]Me Connell SK. Constructing the cerebral co rtex:neurogenesis and fate determ ination[J]. Neuron,1995,(15):761-768.
[46]张绍梅，王素娥，彭争荣等.脑出血模型大鼠针刺穴位合其血清对脑源性神经干细胞膜 相关蛋白Numb表达的影响[J].医学临床研究，2007,24(9):1464-1467
[47]Ghysen A,Dambly-Chaudiere C,Jan LY,et al.Cell interactions and gene interactions in peripheral neurogenesis[J].Genes Dev.1993,7:723-733.
[48]Ken-ichi M,Keejung Y,Louis D,et al.Differential Notch signalling distinguishes neural stem cells from intermediate progenitors[J].Nature,2007,449(20):351-356.
[49]Motoshi N,Michiya S,Masato N.Cross Talk between Notch and Growth Factor/Cytokine Signaling Pathways in Neural Stem Cells[J].Molecular and cellular biology,2007,27(11): 3982-3994.
[50]Hiromi S,Toshiyuki O,Ryoichiro K.Oscillations in notch signaling regulate maintenance of neural progenitors[J].Neuron,2008,58(1):52-64.
[51]Imai T,Tokunaga A,Yoshida T,et al.The neural RNA-binding protein Musashil translationally regulates mammalian numb gene expression by interacting with its Mrna[J]. Molecular and Cellular Biology,2001,21(12):3888-3900.
[52]Okano H,Kawahara H,Toriya M,et al.Function of RNA-binding protein Musashi-1 in stem cells[J].Experimental Cell Research,2005,306(2):349-356.
[53]Watanabe K,Kondo K,Takeuchi N,et al.Musashi-1 expression in postnatal mouse olfactory epithelium[J].Neuroreport,2007,18(7):641-644.
[2]Michael K,Morgan, Lali HS.Sekhon,etal.Defining the role of capillaries in "nornal perfusion pressure breakthrough,"and"occlusive hyperemia"[J].Clin Neurol Neurosurgery, 1997;99:13.
[3]Ni JW,Matsumoto K,Li HB, et al.Neuronal damage and decrease of central acetylcholine level following permanent occlusion of bilateral common carotid arteries in rat[J].Brain Res,1995,673(2):290-6.
[4]Bennett SA,Tenniswood M,Chen JH,etal.Chronic cerebral hypoperfusion elicits neuronal apoptosis and behavioral impairment[J].Neuroreport,1998,9:161-6
[5]Sarti C, Pantoni L, Bartolini L, et al. Cognitive impairment and chronic cerebral hypoperfusion:What can be learned from experimental models[J].Neuro Sci,2002,203-204: 263-6
[6]Li MW,Yi FH,Xi CT.Huperzine A improves cognitive denficits caused by chronic cerebral hypoperfusion in rats[J]. Eur J Pharmacol,2000,398:65-72
[7]Bischormer R,Adjodah D.Long-term expression of heme oxygenase-1 (hsp-32) following focal cerebral infarctions and traumatic brain injury in humans[J].Acta Neuropathologica, 2000,100(04):377-384
[8]Torre DL,Cada JC, Nelson A, etal. Reduced cytochmme oxidase and memory dysfunction after chronic brain ischemia in aged rats[J]. Neurosci Lett,1997,223:165-8
[9]Gehrmann J,Banati RB,Wiessner C.Reactive microglia in cerebral ischemia:an early mediator of tissur damage[J].Neuropathology and Applied Neurobiology,1995,21:277-289.
[10]XiaoZhen Zhao, Wei Wang.ZhongHan Kang etal. structural changes in the hippocampal synapse of rats with vascular dementia [J].Chinese Journal of Clinical Rehabilization, 2003,7(311):4213-15.
[11]Chen Y.Neuronal Synaptic Plasticty,Learning and Memory[J]. Progress in biochemistry and Biophysics [J].2008,35(6):610-619.
[12]Santolini E,Puri C,Salcini AE, etal.Numb is an endocytic protein[J].Cell Biol,2000,151(6): 1345-51.
[13]Wodarz A. Molecular control of cell polarity and asymmetric cell division in Drosophila neuroblasts[J].Curr Opin Cell Biol,2005,17(5):475-81.
[14]Cayouette M,Raff M.Asymmetric segregation of Numb:a mechanism for neural specification from Drosophila to mammals[J].Nat Neurosci,2002,5(12):1265-9.
[15]Karaczyn Aldona,Bani-Yaghoub Mahmud,Tremblay Roger,etal.Two novel human NUMB isoforms provide a potential link between development and cancer[J].Neural Development, 2011,5(1).
[16]De la Torre, J.C. Vascular basis of Alzheimer's pathogenesis[J].Ann. N. Y. Acad.2002. 977,196-215.
[17]Borroni B,Anchisi D,Paghera B.Combined 99mTc-ECD SPECT and neuropsychological studies in MCI for the assessment of conversion to AD[J].Neurobiology of Aging,2006,27: 24-31.
[18]De Jong-GI, Farkas E, Stienstra CM, et al. Cerebral hypoperfusion yields capillary damage in the hippocampal CA1 area that correlates with spatial memory impairment.[J]. Neuroscience,1999,91(1):203-210.
[19]Farkas E,Luiten PG,Bari F,et al.Permanent, bilateral common carotid artery occlusion in the rat:a model for chronic cerebral hypoperfusion-related neurodegenerative diseases.[J].Brain Research Reviews,2007,54(1):162-180
[20]XiaoZhen Zhao, Wei Wang, ZhongHan Kang et al. structural changes in the hippocampal synapse of rats with vascular dementia [J].Chinese Journal of Clinical Rehabilization, 2003,7(311):4213-15.
[21]Dawson D.A., Hallenbeck J.M. Acute focal ischemia-induced alterations in MAP2 immunostaining:description of temporal changes and utilization as a marker for volumetric assessment of acute brain injury[J].Cereb Blood Flow Metab.1996,16,170-174.
[22]Friedrich P, Aszodi A. MAP2:a sensitive cross-linker and adjustable spacer in dendritic architecture[J]. FEBS Lett.1991,295:5-9.
[23]Liu H X, Zhang JJ, Zheng P, et al. Altered expression of MAP-2, GAP-43, and synaptophysin in the hippocampus of rats with chronic cerebral hypoperfusion correlates with cognitive impairment[J]. Brain Res.2005.139,169-177.
[24]刘秀丽.基于GFP的FRET监测树突棘钙动力学[D].华中科技大学,2005.
[25]Cayouette M, Raff M, Asymmetric segregation of Numb:a mechanism for neural specification from Drosophila to mammals[J].Nat Neurosci,2002,5(12):1265-9.
[26]Nishimura T, Fukata Y, Kato K, et al.CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth[J]. Nat Cell Biol,2003,5(9):819-26
[27]Nishimura T,Kaibuchi K.Numb controls integrin endocytosis for directional cell migration with aPKC and PAR-3[J].Dev Cell,2007;13(1):15-28
[28]Kyriazis, GA,Wei, Z,Vandermey, M et al.Numb Endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoform-dependent manner-Implications for Alzheimer disease pathogenesis[J].The Journal of Biological Chemistry,2008,283(37):25492-25502
[29]Thomas S.Ritter B,Verbich D,et al.Intersectin regulates dendritic spine development and somatodendritic endocytosis but not synaptic vesicle recycling in hippocampal neurons[J], Biol Chem,2009,284(18):12410-9.3.
[30]Nishimura T,Yamaguchi T,Tokunaga A,et al.Role of numb in dendritic spine development with a Cdc42 GEF intersectin and EphB2[J]. Mol Biol Cell,2006,17(3):1273-85.3.
[31]Lu CB,Fu W,Xu X et al.Numb-mediated neurite outgrowth is isoform-dependent, and requires activation of voltage-dependent calcium channels.[J].Neuroscience,2009,161(2): 403-412.
[32]Fukata Y,Itoh TJ,Menager C, etal.CRMP-2 binds to tubulin heterodimers to promote microtubule assembly[J].Nat Cell Biol 2002,4(8):583-91.5.
[33]ZhouY,Atkins JB,Rompani SB, etal.The mammalian golgi regulates numb signaling in asymmetric cell division by releasing ACBD3 during mitosis[J].Cell,2007,129(1):163-78.
[34]Chapman G, Liu LN,Sahlgren C，etal.High levels of Notch signaling down-regulate Numb and Numblike[J].Cell Bilo,2006,175(4):535-40.
[35]Bart lett PF, Brook er GJ, Fau x CH, et al. Regu lat ion of neural stem cell dif ferent iat ion in the forebrain[J]. Immunol Cell Biol,1998,76:414～418.
[36]Mc Connell SK. Constructing the cerebral co rtex:neurogenesis and fate determ ination[J]. Neuron,1995,(15):761-768.
[37]Ghysen A,Dambly-Chaudiere C,Jan LY,et al.Cell interactions and gene interactions in peripheral neurogenesis[J].Genes Dev,1993,7:723-733.
[38]张绍梅,王素娥,彭争荣等.脑出血模型大鼠针刺穴位后其血清对脑源性神经干细胞膜相关蛋白Numb表达的影响[J].医学临床研究,2007,24(9)：1464-1467.
[39]Kyriazis GA, Wei Z, Vandermey M, et al. Numb endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoformdependent manner: implications for Alzheimer disease pathogenesis[J]. Biol Chem,2008,283:25492-502.
[40]Koo EH, Squazzo SL. Evidence that production and release of amyloid beta-protein involves the endocytic pathway[J].Biol Chem,1994,269:17386-9.
[41]Chan SL,Pedersen WA,Zhu H.Numb modifies neuronal vulnerability to amyloid beta-peptide in an isoformspecific manner by a mechanism involving altered calcium homeostasis:implications for neuronal death in Alzheimer's disease[J].Neuromoleculdar Mod,2002,1:55-67
[1]Verdi JM, Bashirullah A, Goldhawk DE, et al. Distinct human NUMB isoforms regulate differentiation vs. proliferation in the neuronal lineage[J]. Proc Natl Acad Sci USA, 1999,96:10472-6.
[2]Nie J, McGill MA, Dermer M, etal. LNX functions as a RING type E3 ubiquitin ligase that targets the cell fate determinant Numb for ubiquitin-dependent degradation[J]. EMBO, 2002,21:93-102.
[3]Kyriazis GA, Wei Z, Vandermey M,et al. Numb endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoformdependent manner: implications for Alzheimer disease pathogenesis[J].Biol Chem,2008,283:25492-502.
[4]Karaczyn Aldona,Bani-Yaghoub Mahmud,Tremblay Roger,etal.Two novel human NUMB isoforms provide a potential link between development and cancer[J].Neural Development, 2011,5(1).
[5]Nishimura T, Yamaguchi T, Kato K, etal. PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiaml[J]. Nat Cell Biol,2005,7:270-277.
[6]Ong CT, Cheng HT, Chang LW, etal. Target selectivity of vertebrate notch proteins. Collaboration between discrete domains and CSL-binding site architecture determines activation probability[J]. Biol Chem,2006,281:5106-5119.
[7]Tirnauer JS. A new cytoskeletal connection for APC:linked to actin through IQGAP[J]. Dev Cell,2004,7:778-780.
[8]Chenn A,Mcconnell SK.Cleavage orientation and the asymetric inheritance of Notch 1 immunoreactivity in mammalian neurogenesis[J].Cell,1995,82(4):631-41.
[9]Konno D,Ahioi G,Shitamukai A, etal.Neuroepithelial porgenitors undergo LGN-dependent planar divisions to maintain self-renewability during mammalian neurogenesis[J].Nat Cell Biol 2008,10(1):93-101.
[10]E. Santolini, C. Puri, A.E. Salcini, etal.Numb is an endocytic protein[J]. Cell Biol.2000, 151:1345-1352.
[11]J.A. Knoblich, Mechanisms of asymmetric stem cell division[J].Cell,2008,132:583-597.
[12]Petersen PH,Tang HY,Zou KY,etal.The enigma of the Numb-Notch relationgship during mammalian embryogenesis[J].Dev Neurosci,2006,28(1-2):156-68.
[13]McGill MA, McGlade CJ. Mammalian numb proteins promote notchl receptor ubiquitination and degradation of the notch 1 intracellular domain[J].Biol Chem,2003,278 (25):23196-203.
[14]Chapman G,Liu LN,Sahlgren C,etal.High levels of Notch signaling down-regulate Numb and Numblike[J].Cell Bilo,2006:175(4):535-40.
[15]T. Ito, H.Y. Kwon, B. Zimdahl, etal. Regulation of myeloid leukaemia by the cell-fate determinant Musashi[J], Nature,2010,466:765-768.
[16]C. Zhao, A. Chen, C.H. Jamieson, etal. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia[J], Nature,2009,458:776-779.
[17]C. Dierks, R. Beigi, G.R. Guo, etal. Expansion of Bcr-Ablpositive leukemic stem cells is dependent on Hedgehog pathway activation[J].Cancer Cell,2008,14:238-249.
[18]L. Lanzetti, P.P. Di Fiore, Endocytosis and cancer:an'insider'network with dangerous liaisons[J].Traffic,2008,9:2011-2021.
[19]Singh, J. Settleman, EMT, cancer stem cells and drug resistance:an erging axis of evil in the war on cancer[J].Oncogene,2010,29:4741-4751.
[20]P.B. Gupta, C.L. Chaffer, R.A. Weinberg.Cancer stem cells:mirage or reality[J].Nat.Med. 15 (2009)1010-1012.
[21]Nassar A,Sexton D,Cotsonis G,etal.Survivin expression in breast carcinoma:Correlation with apoptosis and prognosis[J].Appl Immunohistochem Mol Morphol,2008,16(3):221.
[22]Colaluca IN, Tosoni D, Nuciforo P,et al. Numb controls p53 tumour suppressor activity [J]. Nature,2008,451(7174):76-80.
[23]Santolini E,Puri C,Salcini AE,etal.Numb is an endocytic protein[J]. Cell Biol,2000;151(6): 1345-51.
[24]Fukata Y,Itoh TJ,Menager C,Nishimura T,Shiromizu T etal.CRMP-2 binds to tubulin heterodimers to promote microtubule assembly.Nat Cell Biol 2002,4(8):583-91.
[25]Nishimura T, Fukata Y, Kato K, et al. CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth[J]. Nat Cell Biol,2003,5(9):819-26.
[26]XiaoZhen Zhao,Wei Wang,ZhongHan Kang etal. structural changes in the hippocampal synapse of rats with vascular dementia [J].Chinese Journal of Clinical Rehabilization,2003, 7(311):4213-15.
[27]Dendritic morphology of neurons in medial prefrontal cortex and hippocampus in 2VO rats
[28]Sengar, A. S., Wang, W., Bishay, J.etal. The EH and SH3 domain Ese proteins regulate endocytosis by linking to dynamin and Eps15[J], EMBO,1999,18:1159-1171.
[29]Tokumitsu, H., Hatano, N., Inuzuka, H., etal. Phosphorylation of Numb family proteins. Possible involvement of Ca2_/calmodulin-dependent protein kinases.[J]. Biol. Chem. 2005,280:35108-35118.
[30]Govek, E. E., Newey, S. E., and Van Aelst, L.. The role of the Rho GTPases in neuronal development[J]. Genes Dev.2005,19:1-49.
[31]Penzes P, Beeser A, Chernoff J, etal. Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin[J]. Neuron,2003, 37:263-274.
[32]Huang Eric J,Li Huashun,Tang Amy,etal.Targeted deletion of numb and numblike in sensory neurons reveals their essential functions in axon arborization[J]. Genes Dev,2005, 19:138-151.
[33]Pedersen WA, Chan SL, Zhu H,etal. Numb isoforms containing a short PTB domain promote neurotrophic factor-induced differentiation and neurotrophic factor withdrawal-induced death of PC12 Cells[J]. Neurochem,2002,82:976-986.
[34]Ronn LCB.,Dissing S.,Holm A. et al.Increased intracellular calcium is required for neurite outgrowth induced by a synthetic peptide ligand of NCAM[J].FEBS Letters,2002,518(1/3): 60-66
[35]Lu CB,Fu W,Xu X et al.Numb-mediated neurite outgrowth is isoform-dependent, and requires activation of voltage-dependent calcium channels.[J]. Neuroscience,2009,161(2): 403-412.
[36]Kyriazis GA, Wei Z, Vandermey M, et al. Numb endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoformdependent manner: implications for Alzheimer disease pathogenesis[J]. Biol Chem 2008;283:25492-502.
[37]Koo EH, Squazzo SL. Evidence that production and release of amyloid beta-protein involves the endocytic pathway[J]. Biol Chem 1994;269:17386-9.
[38]ZhouY,Atkins JB,Rompani SB, etal.The mammalian golgi regulates numb signaling in asymmetric cell division by releasing ACBD3 during mitosis[J]. Cell 2007;129(1):163-78.
[39]NiggErichA.Cyclin-dependent protein kinases:key regulators of the eukaryotic cell cycle [J].Bioessays,1995,17(6):471-80.
[40]Dho Sascha E,Jacob Sara,Wolting Cheryl D,etal.The mammalian Numb phosphotyrosine-binding domain characterization of binding specificity and identification of a novel PDZ domain-containing numb binding protein,LNX[J].THE JOURNAL OF BIOLOGICAL CHEMISTRY,1998,273(15):9179-9187.
[41]Rice Dennis,Northcutt Grace M,Kurschner Cornelia.The LNX Family Proteins Function as Molecular Scaffolds for Numb Family Proteins [J].Molecular and Cellular Neuroseienee, 2001,18:525-540.
[42]Sollerbrant Kerstin,Raschperger Elisabeth,Mriza Momina,etal.The Coxsackievirus and Adenovirus Receptor(CAR) Forms a Complex with the PDZ Domain-containing Protein Ligand-of-Numb Protein-X(LNX)[J].THE JOURNAL OF BIOLOGICAL CHEMISTRY, 2003,Vol.278,No.9(February 28):7439-7444.
[43]ShuFang, LvShun, QinYan, etal.Functional characterization of human PFTK1 as a cyclin-dependent kinase [J].PNAS,2007,104(22):9248-9253.
[44]Bart lett PF, Brook er GJ, Fau x CH, et al. Regu lat ion of neural stem cell dif ferent iat ion in the f orebrain [J]. Immunol Cell Biol,1998,76:414～418.
[45]Me Connell SK. Constructing the cerebral co rtex:neurogenesis and fate determ ination[J]. Neuron,1995,(15):761-768.
[46]张绍梅，王素娥，彭争荣等.脑出血模型大鼠针刺穴位合其血清对脑源性神经干细胞膜 相关蛋白Numb表达的影响[J].医学临床研究，2007,24(9):1464-1467
[47]Ghysen A,Dambly-Chaudiere C,Jan LY,et al.Cell interactions and gene interactions in peripheral neurogenesis[J].Genes Dev.1993,7:723-733.
[48]Ken-ichi M,Keejung Y,Louis D,et al.Differential Notch signalling distinguishes neural stem cells from intermediate progenitors[J].Nature,2007,449(20):351-356.
[49]Motoshi N,Michiya S,Masato N.Cross Talk between Notch and Growth Factor/Cytokine Signaling Pathways in Neural Stem Cells[J].Molecular and cellular biology,2007,27(11): 3982-3994.
[50]Hiromi S,Toshiyuki O,Ryoichiro K.Oscillations in notch signaling regulate maintenance of neural progenitors[J].Neuron,2008,58(1):52-64.
[51]Imai T,Tokunaga A,Yoshida T,et al.The neural RNA-binding protein Musashil translationally regulates mammalian numb gene expression by interacting with its Mrna[J]. Molecular and Cellular Biology,2001,21(12):3888-3900.
[52]Okano H,Kawahara H,Toriya M,et al.Function of RNA-binding protein Musashi-1 in stem cells[J].Experimental Cell Research,2005,306(2):349-356.
[53]Watanabe K,Kondo K,Takeuchi N,et al.Musashi-1 expression in postnatal mouse olfactory epithelium[J].Neuroreport,2007,18(7):641-644.