本文選題：Rho激酶 + 微管�。� 參考：《南方醫(yī)科大學》2007年博士論文

【摘要】： 目的和意義: 神經(jīng)系統(tǒng)是由數(shù)千億神經(jīng)元通過突觸連接形成的一個既精確又復雜的神經(jīng)網(wǎng)絡。神經(jīng)元的發(fā)育過程中,經(jīng)歷了從分化、遷移、極化、定向生長到與靶細胞建立突觸聯(lián)系的動態(tài)過程。其突起末端的生長錐感受細胞外生長和導向信息,通過微管和微絲運動使細胞形成樹突和軸突,并不斷生長、延伸或坍塌。細胞骨架系統(tǒng)不斷進行重排是細胞突起生長、確定方向和遷移的關鍵。Rho家族的鳥苷三磷酸酶(Rho GTPases)是調(diào)節(jié)細胞骨架運動的主要信號,細胞外生長和導向因子首先通過細胞膜上相應的受體啟動Rho激酶,進而通過坍塌反應調(diào)節(jié)蛋白(CRMPs)影響細胞骨架的重排,如微管和微絲的聚合和解聚,而細胞骨架重排的結(jié)果是神經(jīng)元突起的生長、延伸或坍塌。神經(jīng)系統(tǒng)發(fā)育過程中賦予神經(jīng)元復雜的結(jié)構(gòu)及其它們形成的精確的神經(jīng)網(wǎng)絡構(gòu)成了神經(jīng)系統(tǒng)功能活動的基礎,神經(jīng)元的發(fā)育不僅是從幼小到成熟的過程,也涉及損傷后的修復和再生過程,神經(jīng)組織損傷后突起的再生過程也被認為是其發(fā)育過程的再現(xiàn)。探討Rho激酶通路對神經(jīng)元突起生長和微管重排的調(diào)節(jié)不僅有助于理解神經(jīng)損傷后的再生過程,也可以加深對神經(jīng)退行性病變發(fā)生的認識,使我們有機會找到克服神經(jīng)組織再生和修復困難的新思路和干預靶點。 材料和方法: 實驗首先以發(fā)育不同階段的大鼠海馬為對象,提取總RNA,用RT-PCR的方法檢測大鼠海馬發(fā)育過程中突起生長導向因子GAP-43、Nogo-A、netrin-1、Sema 3A和Nrp-1 mRNA,以及Rho通路信號分子Rho A、Rac-1、CRMP-1和Tubβ3 mRNA的表達水平。進而以原代大鼠海馬神經(jīng)元為對象,用Rho激酶促進劑LPA和抑制劑Y27632干預海馬神經(jīng)元,LPA和Y27632的濃度200ng/ml,原子力顯微鏡觀察細胞突起的生長,并提取突起進行定量;共聚焦顯微鏡觀察細胞微管的重排,并對粘附蛋白vinculin進行亞細胞定位和分布特征進行觀察。實驗進一步構(gòu)建Rho激酶的下游信號CRMP-1的重組體,用非定向克隆技術(shù)構(gòu)建CRMP-1-phrGFPⅡ-N真核表達載體,陽性脂質(zhì)體法轉(zhuǎn)染NGF誘導分化的PC12細胞,觀察CRMP-1對細胞突起生長的影響。 結(jié)果: (1)大鼠海馬發(fā)育過程中生長導向因子和Rho通路信號分子mRNA的表達 大鼠海馬的發(fā)育過程中,生長因子GAP-43 mRNA胚胎和新生階段表達較多,幼年和成年階段表達較少(P＜0.05),老年階段表達仍維持較高水平;Nogo-A在胚胎階段表達較多,出生后和GAP-43相似,成年和老年階段處于高峰時期。導向因子netrin-1以胎鼠、新生鼠和成年鼠表達最強,幼年和老年階段表達較少。Sema 3A隨著海馬發(fā)育逐漸降低,但其受體Nrp-1從幼年到老年表達逐漸增多。信號分子Rho-A和Rac-1的表達與Rho-A的表達有相似的變化規(guī)律,隨著海馬發(fā)育亦呈明顯的階段性,表達的高峰在胚胎、幼年和老年階段,而新生階段和成年階段處于相對低表達階段;Rac-1的表達量在海馬發(fā)育的各個階段均超過Rho-A的表達量。CRMP-1和tubulin的表達從胚胎到成年的各個階段與CRMP-1的表達具有相似的變化趨勢,以胎鼠、新生大鼠和幼年大鼠表達較多,但老年階段CRMP-1的表達較成年階段顯著升高(P＜0.05),而tubulin在老年階段停留在成年階段的水平。 (2)Rho激酶對大鼠海馬神經(jīng)元突起生長和微管重排的調(diào)節(jié) 原子力顯微鏡的觀察顯示,LPA處理組海馬神經(jīng)元突起的數(shù)量減少,一些突起僅見殘留的突起根部,一至三級突起的數(shù)目均減少(P＜0.05);LPA預處理后用Y27632干預,雖然胞體的形態(tài)未見明顯的變化,但是一級突起的數(shù)目增多,呈輻射狀從胞體伸出,并伴有豐富的二級突起,一級和二級突起的數(shù)目與對照組相比增多(P＜0.05);提取突起的光密度測定顯示,LPA處理后的細胞較對照組降低(P＜0.05),LPA預處理后用Y27632干預組的細胞較LPA組升高(P＜0.05),與對照組無差異顯著。 共聚焦顯微鏡觀察顯示,海馬神經(jīng)元胞體、突起和生長錐均顯示清晰的微管,LPA干預組突起較短,而且突起遠端的熒光較淺淡;胞體內(nèi)無清晰可見的絲網(wǎng)狀微管,取而代之的是不規(guī)則的微管,其粗細不均,排列不規(guī)整,失去原有的鳥巢樣外觀;突起內(nèi)微管的排列出現(xiàn)發(fā)辮樣改變,成束的微管之間出現(xiàn)較大的縫隙;生長錐失去原有的外貌,僅見突起細小的末端,無典型的生長錐,其中的微管大部分消失。LPA預處理后用Y27632干預,胞體內(nèi)可見較清晰的絲網(wǎng)狀微管,這些微管粗細較均勻,除了圍繞胞核周圍分布的微管外,還可見末端游離的微管,伸入細胞的突起;突起內(nèi)的微管不甚規(guī)整,仍可見微管之間較大的空隙,但較LPA組排列規(guī)整;突起末端生長錐基本保持了原有的形態(tài),呈不典型的扇形突出,其中可見較清晰的微管,它們直行伸入生長錐或者彎曲走行,較長的微管伸入生長錐中心部位,短的微管位于生長錐的根部。vinculin蛋白散在分布于細胞膜上,LPA干預組細胞膜上亦可見綠色熒光點散在分布于細胞膜上;LPA處理后用Y27632干預,細胞膜上分布較密集的綠色熒光,而且這些熒光點常聚集在一起,在細胞膜的周邊區(qū)域和突起的根部分布較密集,顯示vinculin蛋白在細胞膜的周邊聚集。 (3)CRMP-1-phrGFPⅡ-N真核表達載體的構(gòu)建及其對突起生長的調(diào)節(jié) 從大鼠海馬總RNA擴增出的目的基因片斷為1800bp,符合設計片斷的大小;連接轉(zhuǎn)化后形成白色菌落,EcoRⅠ單酶切后的重組體出現(xiàn)1800bp大小的目的基因片斷和3000bp大小的克隆載體片斷,未經(jīng)酶切的重組體為4800bp。雙向測序結(jié)果顯示,CRMP-1目的基因片斷為1746bp,與genbank的序列比對顯示僅4位的堿基突變,不影響翻譯蛋白質(zhì),同源性為99.8%。與表達載體連接后,轉(zhuǎn)化細菌,挑取正向連接克隆,CRMP-1-phrGFPⅡ-N重組體電泳條帶位于6700bp處,酶切后顯示4900bp和1800bp兩個片斷。 50ng NGF誘導后,PCI2細胞突起延長,分化為神經(jīng)元樣細胞。空載體轉(zhuǎn)染組的細胞顯示較強的綠色熒光,熒光分布于胞體和突起,細胞的突起較長。CRMP-1-phrGFPⅡ-N轉(zhuǎn)染組,其熒光與空載體轉(zhuǎn)染組分布相似,主要分布于胞體和突起,但細胞突起較短小,表達CRMP-1的細胞少見超過胞體直徑數(shù)倍的突起,個別較長的突起亦較空載體組短小。 結(jié)論: (1)在大鼠海馬的發(fā)育過程中,胚胎階段GAP-43和Nogo-A處于高表達狀態(tài),出生后回落,老年階段GAP-43仍維持較高水平,而Nogo-A在成年和老年均呈高表達狀態(tài),提示老年階段海馬神經(jīng)元仍具有較強的生長和再生能力,而抑制因子的高表達可能是再生困難的原因。 (2)生長導向因子netrin-1的表達貫穿胚胎、新生、幼年和成年階段,老年表達較低;而Sema 3A主要局限于胚胎和新生階段,但是其受體的表達在經(jīng)歷了新生階段的低表達后逐漸增多的過程。 (3)細胞內(nèi)Rho-A和Rac-1信號分子的發(fā)育雖然在各個階段均有較高的表達,但具有明顯的階段性,新生和成年階段表達相對較低,胚胎、幼年和老年階段相對較高。 (4)微管蛋白的發(fā)育從胚胎到幼年呈逐漸下降的趨勢,成年和老年階段相對穩(wěn)定,CRMP-1的發(fā)育從胚胎到成年階段與微管的發(fā)育經(jīng)歷相似的變化,但是老年階段表達較高。 (5)激活Rho激酶通路可誘導神經(jīng)元突起坍塌,表現(xiàn)在各級突起數(shù)目的減少和長度的縮短,抑制Rho激酶通路可促使神經(jīng)元突起各級分支數(shù)目的增加以及突起的生長。Rho激酶不但通過調(diào)節(jié)微管重排參與突起的生長延長,還參與突起的分支形成,抑制Rho激酶的活性基本能逆轉(zhuǎn)LPA對突起生長的坍塌作用,但并不能完全逆轉(zhuǎn)LPA誘導的微管重排。 (6)擴增了CRMP-1的cDNA,完成CRMP-1-PGEM-T Easy克隆載體和CRMP-1-phrGFPⅡ-N真核表達載體的構(gòu)建。 (7)轉(zhuǎn)染由NGF誘導分化的PC12細胞后,CRMP-1在細胞的胞體和突起表達,導入CRMP-1外源基因的PC12細胞突起明顯縮短,顯示CRMP-1具有抑制突起生長和誘導其坍塌的作用。
[Abstract]:Purpose and significance:
A neural network is an accurate and complex neural network formed by a synapse of hundreds of billions of neurons through synapses. During the development of a neuron, a dynamic process from differentiation, migration, polarization, and directional growth to the target cells. Tube and microfilament movement causes cells to form dendrites and axons, growing, extending or collapsing. The cytoskeleton system constantly rearrangements is the growth of cell protuberances. The key.Rho family of.Rho (Rho GTPases) is the main signal to regulate cytoskeleton movement, and the extracellular growth and guiding factors are first passed. The corresponding receptor on the cell membrane starts the Rho kinase and then affects the rearrangement of the cytoskeleton through the collapse response regulating protein (CRMPs), such as the polymerization and disaggregation of microtubules and microfilaments, and the result of the rearrangement of the cytoskeleton is the growth, extension or collapse of the neurites. The complex structures and their shapes are given to the neurons in the process of the development of the nervous system. The exact neural network constitutes the basis of the functional activity of the nervous system. The development of neurons is not only from young to mature, but also in the process of repair and regeneration after injury. The process of regeneration of the neurites after the injury of the nerve tissue is also considered to be the reproduction of its development process. The growth of the neurites by the Rho kinase pathway and the growth of the neuron are discussed. The regulation of microtubule rearrangement not only helps to understand the process of regeneration after nerve injury, but also helps to deepen the understanding of the occurrence of neurodegenerative diseases, so that we have a chance to find new ideas and targets to overcome the difficulty of regeneration and repair of nerve tissue.
Materials and methods:
First, the total RNA was extracted from the hippocampus of rats at different stages of development. RT-PCR was used to detect the growth guiding factor GAP-43, Nogo-A, netrin-1, Sema 3A and Nrp-1 mRNA in the process of hippocampus development in rats, and the expression level of Rho pathway signal molecule Rho A. Rho kinase promoter LPA and inhibitor Y27632 were used to interfere with hippocampal neurons, LPA and Y27632 concentration 200ng/ml. The growth of cell protuberances was observed by atomic force microscopy, and the protuberances were extracted and quantified. Confocal microscopy was used to observe the rearrangement of cell microtubules and to observe subcellular localization and distribution characteristics of adherent egg white vinculin. The experiment further constructed the recombinant of the downstream signal CRMP-1 of the Rho kinase, and constructed the CRMP-1-phrGFP II -N eukaryotic expression vector by non directional cloning technique. The positive liposome method was transfected to NGF induced PC12 cells, and the effect of CRMP-1 on the growth of the cell protuberance was observed.
Result:
(1) expression of growth orientation factor and Rho pathway signaling molecule mRNA during hippocampus development in rats
During the development of rat hippocampus, the expression of growth factor GAP-43 mRNA embryo and new stage is more, the expression in young and adult stage is less (P < 0.05), the expression of old age is still high, Nogo-A is more expressed in the embryo stage, after birth and GAP-43, and at the peak period of adult and old age. The guide factor netrin-1 is born. The expression of rat, newborn rat and adult rat was the strongest. The expression of.Sema 3A in young and old age decreased gradually with the development of hippocampus, but the expression of its receptor Nrp-1 increased gradually from young to old. The expression of signal molecule Rho-A and Rac-1 was similar to the expression of Rho-A. With the development of hippocampus, the peak of expression was also obvious. In the embryo, the young and the old, the new stage and the adult stage are in the relatively low expression stage; the expression of Rac-1 is more than the expression of Rho-A,.CRMP-1 and tubulin at various stages of the development of the hippocampus. The expression of.CRMP-1 and the expression of the expression from the embryo to the adult is similar to the expression of the expression of the CRMP-1. There was more expression in rats, but the expression of CRMP-1 was significantly higher in the elderly stage than in the adult stage (P < 0.05), while tubulin remained at the adult stage in the elderly stage.
(2) Regulation of Rho kinase on neurite outgrowth and microtubule rearrangement in rat hippocampal neurons
Atomic force microscopy (AFM) showed that the number of neurites in the hippocampal neurons in the LPA treatment group decreased, some of the protuberances were only seen in the residual protuberance, and the number of the first to three protrusions decreased (P < 0.05). LPA was pretreated with Y27632, although the morphology of the cell body was not obviously changed, but the number of primary protuberances increased, showing radiation from the cell body. The number of the first and two stage protrusions increased (P < 0.05), the number of first and two protrusions was increased (P < 0.05). The cells after LPA treatment were lower than the control group (P < 0.05), and the cells in the Y27632 intervention group were higher than those in the LPA group (P < 0.05) after the pretreatment (P < 0.05), and there was no significant difference between the control group and the control group.
The confocal microscope showed that the cells of the hippocampal neurons, the protuberances and the growth cones all showed clear microtubules. The protuberances of the LPA intervention group were shorter, and the fluorescence of the protuberance was lighter. There was no clear visible microtubule in the cell, and the irregular microtubules were replaced with irregular arrangement and lost the original nests. The arrangement of microtubules in the protuberances appeared with braid changes and large gaps between the microtubules of the bundles; the growth cone lost the original appearance, only seen the fine ends and no typical growth cones. Most of the microtubules disappeared after the.LPA preconditioning, and Y27632 was used to intervene in the cells. More evenly, apart from the microtubules around the nucleus of the nucleus, the free microtubules of the end were visible, and the microtubules in the protuberances were not very regular, and the larger spaces between the microtubules were still visible, but they were arranged regularly in the LPA group. The clear microtubules are straight into the growth cone or bend and walk, the longer microtubules reach the central part of the growth cone, the short microtubules are scattered on the cell membrane at the root of the growth cone, and the green fluorescence points are scattered on the cell membrane on the cell membrane of the LPA intervention group; after LPA treatment, the cell membrane is interfered with the cell membrane. The dense green fluorescence is denser, and these fluorescent dots are often gathered together, denser in the surrounding area of the cell membrane and in the root of the protuberance, indicating that the vinculin protein is gathered around the cell membrane.
(3) construction of CRMP-1-phrGFP II -N eukaryotic expression vector and regulation of neurite outgrowth
The target gene fragment amplified from the total RNA of the rat hippocampus was 1800bp, conforming to the size of the design fragment. After the connection was transformed to form a white colony, the 1800bp size target gene fragment and the 3000bp size cloned carrier fragment appeared in the recombinant EcoR I after the single enzyme cut, and the unenzymed recombinant body was shown to 4800bp. bi-directional sequencing results, and CRMP-1 orders were shown. The gene fragment was 1746bp, and the sequence alignment with GenBank showed that only 4 base mutations did not affect the translation of protein. After the homology was connected to the expression vector, the homology was converted to bacteria, and the positive clones were picked up. The CRMP-1-phrGFP II -N recombinant strip was located at 6700bp, and the two fragments of 4900bp and 1800bp were displayed after the enzyme digestion.
After the induction of 50NG NGF, the protuberances of PCI2 cells were extended and differentiated into neuron like cells. The cells in the transfected group showed strong green fluorescence, and the fluorescence was distributed in the cell and the protuberance. The cell protuberance was long.CRMP-1-phrGFP II -N transfection group. The fluorescence of the cells was similar to the distribution of the empty body transfected group, mainly in the cell body and the protuberance, but the cell protruded more. In short, the cells expressing CRMP-1 rarely exceed the diameter of the cell body several times, and some longer protuberances are shorter than empty vectors.
Conclusion:
(1) during the development of hippocampus, the GAP-43 and Nogo-A in the embryonic stage were in high expression state, after birth, the GAP-43 remained high in the aged, while Nogo-A was highly expressed in both adult and old age, suggesting that the hippocampal neurons still have strong growth and regeneration ability in the aged and the high expression of inhibitory factors may be expressed. It's the reason why it's difficult to regenerate.
(2) the expression of growth guiding factor netrin-1 runs through the embryo, newborn, young and adult stage, and the expression of old age is low; and Sema 3A is mainly confined to the embryo and the newborn stage, but the expression of its receptor is gradually increasing after the low expression of the new stage.
(3) the development of Rho-A and Rac-1 signal molecules in cells has high expression at all stages, but it has obvious stages. The expression of new and adult stage is relatively low, and the embryo, young and old age are relatively high.
(4) the development of microtubulin is gradually decreasing from embryo to young age, and the development of adult and old age is relatively stable. The development of CRMP-1 is similar to the development of microtubules from embryo to adult stage, but the expression of old age is higher.
(5) activation of the Rho kinase pathway can induce the collapse of the neurite protuberance, the decrease of the number of protuberances at all levels and the shortening of the length. The inhibition of the Rho kinase pathway can promote the increase of the number of branches at all levels and the growth of the protuberance.Rho kinase not only by regulating the growth of the microtubule rearrangement and the protuberance, but also in the branching branching. Inhibition of Rho kinase activity can basically reverse the collapse of LPA to neurite growth, but it does not completely reverse LPA induced microtubule rearrangement.
(6) amplify the cDNA of CRMP-1, and complete the construction of CRMP-1-PGEM-T Easy cloning vector and CRMP-1-phrGFP II -N eukaryotic expression vector.
(7) after transfection of PC12 cells induced by NGF, CRMP-1 was expressed in cell body and protuberance, and the protuberances of PC12 cells introduced into CRMP-1 were obviously shortened, which showed that CRMP-1 had the effect of inhibiting the growth of protruding and inducing its collapse.
【學位授予單位】：南方醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2007
【分類號】：R338

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