發(fā)育生物學(xué)與再生醫(yī)學(xué)：神經(jīng)系統(tǒng)發(fā)育與神經(jīng)再生

1、Development and Regeneration of the Nervous System 神經(jīng)系統(tǒng)發(fā)育與神經(jīng)再生 講解內(nèi)容： 1. 引言NS的組成回顧 2. NS發(fā)育的基本過程 3. NS發(fā)育的基本機(jī)制 4. 神經(jīng)再生 1. The component of nervous system the Nervous System neurons and synapses in the cerebral cortex The overall process of nervous system development Neural induction（神經(jīng)誘導(dǎo)形成神經(jīng)管neural tub

2、e 和神經(jīng)嵴 neural crest ）specification of neural cell identity（神經(jīng)細(xì)胞分化） migration of neural cell（神經(jīng)細(xì)胞遷移） outgrowth of axons（突起生長） formation of synapses（突 觸形成） programmed cell death （NS發(fā)育階段 特定性細(xì)胞凋亡）. 1) The formation of the neural tube: neural tubebrain development 1) The formation of the neural tube: Not

3、ochord(脊索)induces the ectoderm on dorsal surface of embryo during gastrulation to form the neural plate(神經(jīng)板), and the neural plate begins to fold and form the neural tube(神經(jīng)管). The cells of neural plate: epithelium When the forming of the neural tube, the epithelium differentiate into nerve cell The

4、 cells within the neural tube give rise to the brain and spinal cord, which together comprise the central nervous system Neural tube formation and migration of neural crest cells 2) The migration of neural crest cells: 2) The migration of neural crest cells: Neural crest(神經(jīng)嵴) cells migrate away from

5、 the dorsal half of the neural tube undergoing an epithelial to mesenchymal transition and give to both the sensory neurons of the peripheral nervous system and to the autonomic nervous system. 3) The specification of neural (neuron or glial) cell identity Expression of genes known as proneural gene

6、s（原神經(jīng)基因）initiate neural specification by regulating the transcription of down-stream target genes. Intrinsic differences External signals Drosophila (fruit fly) Neurectoderm(神經(jīng)外胚層) In Drosophila, the presumative central nervous system is specified at an early stage of development as two longitudinal

7、 stripes of cells along the dorso-ventral axis of the embryo. This region is called the neurogenic zone（神經(jīng)發(fā)生區(qū)）or neurectoderm. Expression of genes known as proneural genes, the neurectodermal cells are given the potential to become neural precursors. Of particular importance as proneural genes in Dr

8、osophila are the genes of the achaete- scute complex（毛翅-鱗甲基因復(fù)合體）. 1). Proneural genes（原神經(jīng)基因） Achaete-scute complex Encoding transcription factors, notably the proteins achaete and scute, which have a basic helix-loop-helix (bHLH) DNA-binding motif. These transcription factors form homodimers and het

9、erodimers with each other, and bind to target genes to initiate neural specification. Within neurectoderm, the cells expressing these genes form groups called proneural clusters. basic helix-loop-helix (bHLH) Within the neurectoderm, cells expressing achaete gene form groups called proneural cluster

10、s Pattern of achaete-scute complex expression The correct pattern of expression of achaete-scute depends on a regulatory module that control the pattern of neurogenic gene expression at specific sites. Site-specific expression of achaete and scute depends on combinations of transcription factors bin

11、ding to the regulatory module. Regulatory module of achaete-scute complex Transcription factors Site-specific expression of achaete-scute complex The neurectodermal cells are given the potential to become neural precursors In addition, the pair-rule genes, together with genes expressed along the dor

12、so-ventral axis and the segment polarity gene wingless, are involved in patterning the proneural clusters and distinguishing them from the rest of the neurectoderm, which will become epidermis. 觸發(fā)proneural clusters 形成的其他基因 Achaete-scute complex The pattern of prospective sensory cells within the ima

13、ginal disc（器官芽，成蟲 盤 ） is constructed by the independent action of site-specific regulatory modules along the achaete-scute complex. Functions in PNS（外周神經(jīng)系統(tǒng)） Imaginal disc Are small sacs of epithelium present in the larva of Drosophila and other insects, which at metamorphosis give rise to adult stru

14、ctures such as wings, legs, antennae, eyes, and genitalia. The wings represent a main phenotype in fruit fly Sensory bristles of Drosophila Bristle：剛毛 Specification of sensory neurons in the Drosophila wing Thus has an important role in the speci- fication of the sensory nervous system of the adult

15、fly. Contributing to establishment of CNS and PNS. 小結(jié)：Achaete-scute complex 2) Lateral inhibition allocates neuronal precursors The singling out of the prospective neural cells involves lateral inhibition（側(cè)向抑制）. The lateral inhibition leads to just one cell developing as a neuroblast, with the rest

16、of the cluster becoming epithelial epidermal cells. The role of lateral inhibition in neural cell development Lateral inhibition的定義 Some cells inhibit neighboring cells from developing in a similar way to themselves. 在具有相同分化命運(yùn)的胚胎細(xì)胞中，如果 一個(gè)細(xì)胞“試圖”向某個(gè)特定方向分化，那 么，這個(gè)細(xì)胞在啟動(dòng)分化指令的同時(shí)也發(fā) 出另一個(gè)信號(hào)去抑制鄰近細(xì)胞的分化。 Molecul

17、ar mechanism of lateral inhibition: Notch-Delta interaction In the specification of both central nervous system neurons and sensory organs, the Notch and Delta genes play a key role in lateral inhibition once the proneural clusters have formed. Their activity ensures that just one neuron or sensory

18、organ develops from each cluster at a given time. Notch-Delta interaction Notch-Delta interaction is involved in lateral inhibition 3) Asymmetric cell divisions（細(xì)胞不對(duì)稱分裂） are involved in Drosophila sensory organ development Single neuroblast External sensory organsInternal chordotonal organs are made

19、 up of four cells, one of which is a sensory neuron Chordotonal：脊索的 Are cell divisions in which the daughter cells are different from each other because some cytoplsmic determinants have been distributed unequally between them. 在胚胎早期發(fā)育過程中，細(xì)胞質(zhì)成分是不均質(zhì) 的，胞質(zhì)中某些成分的分布有區(qū)域性。 當(dāng)細(xì)胞分裂時(shí)，細(xì)胞質(zhì)成分被不均等地分配到 子細(xì)胞中，這種不均一性胞

20、質(zhì)成分可以調(diào)控細(xì) 胞核基因的表達(dá)，從而決定細(xì)胞的分化。 細(xì)胞不對(duì)稱分裂：胚胎細(xì)胞分裂時(shí)胞質(zhì)的不均等分配. Sensory nervous system of Drosophila Sensory bristles Asymmetric cell divisions are involved in sensory neuron development Numb is involved in sensory neuron development Asymmetric division during sensory cell development in Drosophila is a very c

21、lear example of cytoplasmic localization involved in cell specification. Drosophila Neurectoderm Sensory neuron Proneural clusters Neuroblast Lateral inhibition by Notch-Delta Asymmetric cell division Proneural gene (achaete-scute) Development of Sensory bristles Dev. Of CNS In vertebrate： Toward th

22、e end of gastrulation（原腸胚形成） , the neural plate begins to fold and form the neural tube， and neural crest cells neural tube brain and spinal cord neural crest cells peripheral nervous system There are similarities in specification of cells as neuronal precursors between vertebrates and Drosophila. L

23、ateral inhibition specifies single cells as neural precursors Interaction of Delta ligand and Notch receptor provides a signal that inhibits neuronal differentiation by inhibiting Neurogenin synthesis. The Neurogenin gene, which codes for a bHLH transcription factor, is related to the achaete and sc

24、ute proteins.（Neurogenin是achaete 和 scute的同源體蛋白）。 Lateral inhibition is involved in the specification of vertebrate neuronal precursors Expression of Neurogenin in one cell leads to the cell expressing neruoD, which codes for a transcription factor required for neuronal differentiation. Asymmetric ce

25、ll divisions (Numb protein) by stem cells generate neurons 2. Neural migration in Vertebrates Neural tube formation Neurons arise from VPZ and neural crest Lateral inhibition Neural migration VPZ：ventricular proliferative zone, 室管膜增 生區(qū) In both brain and spinal cord, all neurons and glia arise from a

26、 proliferative layer of epithelial cells lining the lumen of neural tube, called ventricular proliferative zone (VPZ). 放射狀遷移（radial migration)： 是神經(jīng)元沿垂直于腦表 面的方向遷移，是大腦皮層發(fā)育早期神經(jīng)元的主要遷移模式。 Neural migration during the brain development VZ: 室管膜增生區(qū)增生區(qū) SVZ: 室管膜下層 IZ: 中間帶 SP: 底板 CP: 皮質(zhì)板 MZ: 邊緣帶 PS: 軟腦膜表面 RGC:

27、放放射狀神經(jīng) 膠質(zhì)細(xì)胞 切線位遷移（tangential migration)： 指神經(jīng)元沿著 與腦表面平行的方向遷移，是大腦皮層發(fā)育晚期，在皮質(zhì) 板（cortical plate）形成后的主要遷移模式。 Mechanism of of cerebral cortex cell migration Reelin is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing bra

28、in by controlling cellcell interactions. Mutations in Reelin disrupts migration and proper Mutations in Reelin disrupts migration and proper cerebellar cortical layers do not form.cerebellar cortical layers do not form. Neural crest cells migration Neural crest cells migrate away from the neural tub

29、e, giving rise to a wide variety of different cell types including cartilage in the head, pigment cell in the dermis, medullary cells in the adrenal gland, glial Schwann cells, neurons of peripheral nervous system neurons of autonomic nervous system The outgrowth of axons to their targets is followe

30、d by formation of synapses with the target cellswhich can be other neurons, muscle or gland cells The growth cone（生長錐） controls the axon growing Growth cone: The motile tip of the axon or dendrite of a growing nerve cell, which spreads out into a large cone-shaped appendage. A cultured sensory neuro

31、n extending a growth cone with lamellipodia and filopodia 生長錐是軸突延伸生長過程的末端膨 大，是發(fā)育神經(jīng)元引導(dǎo)軸突前端的結(jié) 構(gòu)，包括絲狀偽足（filopodia）和片狀 偽足（lamellipodia）. An early event in the differentiation of a neuron is the extension of its axon by the growth cone at the axon tip. The growth cone can continually extend and retract f

32、ilopodia, which help to pull the axon tip forward over the underlying substratum. 生長錐內(nèi)有微管蛋白（負(fù)責(zé)運(yùn)輸小泡到生長錐）。 生長錐內(nèi)含肌動(dòng)蛋白和肌球蛋白（負(fù)責(zé)提供生長錐移動(dòng)的收縮力）。 The activity of the growth cone guides axon outgrowth, and is influenced by the contacts the filopodia make with other cell and with the extracellular matrix. 生長錐突起

33、上有許多膜受體，可接 受神經(jīng)遞質(zhì)和某些蛋白酶的作用， 并通過電壓依賴的Ca2+通道對(duì)生長 錐膜興奮性產(chǎn)生影響。 Axon growth cones are guided by two main types of cueattractive and repulsive. Axon pathway depends on envionmental cues and neuronal identity 特定位置細(xì)胞分泌的可擴(kuò)散 性旁分泌因子及其提供的濃 度梯度在引導(dǎo)軸突生長中起 重要作用，可表現(xiàn)為吸引及 排斥性趨化效應(yīng)。 旁分泌因子Slit、 Ephrins、Netrins和導(dǎo)向蛋 白Semaphor

34、ins等既可影 響神經(jīng)元的遷移，又對(duì)軸 突的生長有導(dǎo)向作用。 Basic process of 1) synaptogenesis(突觸發(fā)生) 軸突到達(dá)靶點(diǎn)后，按照競爭排斥的原則與靶細(xì)胞形成突 觸的過程。 2） synaptodifferentation(突觸分化) 突觸前膜、突觸間隙及突觸后膜的形態(tài)發(fā)生。 3） synaptorearrangement(突觸重排) 該過程經(jīng)歷很長時(shí)間，本質(zhì)是突觸前膜與突觸后膜 的電活動(dòng)一致。 4） synaptoregressive(突觸消退) 多余突觸的消失。 The refinement of synaptic connections, through

35、the elimination of axon branches and by programmed cell death 神經(jīng)發(fā)育異常： 神經(jīng)管閉合不全：脊柱裂。 大腦皮層發(fā)育異常：頭小畸形、局灶性 皮質(zhì)發(fā)育不良、側(cè)巨腦癥； 神經(jīng)易位、 無腦回畸形；多小腦回和腦裂；結(jié)節(jié)狀 硬化癥。 5. Neural regeneration（神經(jīng)再生） （一）外周神經(jīng)（PNS）再生 現(xiàn)象： PNS受損后，被切斷的神經(jīng)纖維可產(chǎn)生一系列被稱為 斷離神經(jīng)纖維脂肪變性（wallerian degeneration）的 特征性變化： 髓鞘和軸索（突）崩解破碎、殘?bào)w被吞噬消除， 但包括神經(jīng)纖維的施旺細(xì)胞（Schwan

36、n cell）仍保持活 力。 在損傷3個(gè)月之后，整個(gè)神經(jīng)纖維能完成修復(fù) （再生）。 PNS再生過程： PNS再生機(jī)制：主要是施旺細(xì)胞對(duì)軸突延伸的引導(dǎo)。 受損神經(jīng)軸突退化潰變、髓鞘破碎分 解成許多卵圓形殘?bào)w，隨機(jī)被侵入的巨噬 細(xì)胞吞噬； 潰變周圍的施旺細(xì)胞開始分裂增殖，并 形成血多飾帶（cordon），構(gòu)成軸突修復(fù) 延伸的管道； 在損傷處神經(jīng)細(xì)胞的胞體端，軸突形成 一個(gè)或多個(gè)生長錐，并進(jìn)入施旺細(xì)胞管 道，通過生長錐不斷延伸，直至與遠(yuǎn)端靶 細(xì)胞重新連接。 （二）中樞神經(jīng)（CNS）再生 1. CNS軸突再生的抑制 現(xiàn)象： CNS中軸突被切斷后，在最初有生長現(xiàn)象， 但隨后便逐漸退化了。 若將CNS中神

37、經(jīng)元軸突移植到外周神經(jīng) 中，發(fā)現(xiàn)受損的軸突可繼續(xù)生長。 以上現(xiàn)象提示：中樞神經(jīng)的軸突不能再生可 能與它處在抑制其再生的環(huán)境有關(guān)。 機(jī)制：一些具有促進(jìn)軸突生長的蛋白因子可在胚胎發(fā)育和PNS中表達(dá)，但在CNS中 不表達(dá)；相反在CNS損傷處有大量的軸突再生抑制因子. 少突膠質(zhì)細(xì)胞表達(dá) 軸突再生抑制因子： Nogo, MAG(myelin-associated glycoprotein), CSPG(chondroitin sulfate proteoglycan), Arretin. 星形膠質(zhì)細(xì)胞被激活后形成神經(jīng)膠質(zhì)疤痕（glial scar）,其中含多種軸突延伸抑制 因子：Tenascin,Ker

38、atin,CSPG;致使延伸的軸突被阻止，而形成收縮球（retraction bulb）. 2. CNS中成體神經(jīng)干細(xì)胞的存在說明有再生的潛 能，但臨床上未見有病變損傷的神經(jīng)元得到修 復(fù)或補(bǔ)充 此種現(xiàn)象的機(jī)制，有待研究。 3. CNS受損后的再生修復(fù)策略 1）消除軸突再生抑制因子的作用； 2）應(yīng)用體外培養(yǎng)的神經(jīng)干細(xì)胞進(jìn)行細(xì)胞替換（目前是腦內(nèi) 注射）； 3）深入探討CNS內(nèi)成體（或組織）神經(jīng)干細(xì)胞的譜系維持 及誘導(dǎo)分化機(jī)制，為尋找潛在干預(yù)靶點(diǎn)打基礎(chǔ)； 4）探討選擇性開放血腦屏障（BBB）的機(jī)制，為向腦內(nèi)無 創(chuàng)傷性輸送神經(jīng)細(xì)胞提供潛在技術(shù)手段。 腦血管的發(fā)育與大腦發(fā)育的關(guān)系 ？ 腦血管的總長度 6

39、00-700公里 A Cast of the Microvascular Network and Two-Photon In Vivo Imaging of the Mouse Brain Microcirculation A Simplified Molecular Atlas of the BBB Schematic of the Neurovascular Unit Nearly every neuron in human brain has its own capillary The total length of capillaries in human brain is about

40、 400miles 4) The migration of neurons and the outgrowth of axons to their targets All cortical neurons have their origin in the ventricular proliferative zone（VPZ，室管膜增生 區(qū)）, and migrate outward to their final positions along radial glial cells（放射狀膠質(zhì)細(xì) 胞, RGC細(xì)胞）. 大腦皮質(zhì)的組織發(fā)生：發(fā)生于室管膜層（室層） 從時(shí)間上：大腦皮層的分 化順序?yàn)楣?/p>

41、皮質(zhì) （archicortex,海馬和齒狀 回）、舊皮質(zhì) （paleocortex）、新皮質(zhì) （neocortex）. 從組織上：大腦皮層表現(xiàn) 為有特定神經(jīng)元分布的板層 結(jié)構(gòu). 邊緣層內(nèi)含Cajal-Retzius 細(xì)胞（C-R細(xì)胞），它分泌 細(xì)胞外基質(zhì)蛋白reelin. The outgrowth of axons to their targets, the formation of synapses with the target cellswhich can be other neurons, muscle or gland cells 原發(fā)誘導(dǎo)（Primary induction） ：

42、指形成神經(jīng)板的誘導(dǎo)。其本質(zhì)是中胚 層向外胚層釋放神經(jīng)化因子（neurolizing factor）,促使外胚層向具有神經(jīng)組織特 異性轉(zhuǎn)變。 次發(fā)誘導(dǎo)（Secondary induction ）：指形成早期腦與脊髓的誘導(dǎo)。其 本質(zhì)是中胚層通過與具有預(yù)定發(fā)育為神經(jīng)系統(tǒng)的外胚層互作（直接接觸或分泌因 子）：中胚層前部與外胚層互作誘導(dǎo)出前腦；中胚層中部與外胚層互作誘導(dǎo)出中 腦和后腦；中胚層最后部與外胚層互作誘導(dǎo)出脊髓。 機(jī)制：Dorsal signals (e.g. BMP-4) and Ventral signal (Sonic hedgehog) pattern neural tube 中胚層分泌

43、的神經(jīng)誘導(dǎo)因子： 誘導(dǎo)前端神經(jīng)組織而不誘導(dǎo)后端結(jié)構(gòu)的 因子：Noggin、follistatin、chordin和 cerberus, 其功能是起到BMP（bone morphagenetic protein )抑制劑作用。 其他誘導(dǎo)因子：Notch、Wnt、FGF、 HGF、Dorsalin和Hedgehog. 神經(jīng)管的演 變（側(cè)面觀 及冠狀切面 觀） 神經(jīng)管的組織發(fā)生(histogenesis/ tissue organization) 最初神經(jīng)管管壁是由一層較厚的假復(fù)層上皮細(xì)胞組成，稱為神經(jīng)上皮細(xì)胞 （neuroepithelium）。 隨神經(jīng)上皮不斷增值，分裂后的一個(gè)子細(xì)胞向神經(jīng)上皮的

44、外周遷移，分化 為成神經(jīng)細(xì)胞（neuroblast）, 形成套層（mantle layer）,各種類型的神 經(jīng)元和神經(jīng)膠質(zhì)細(xì)胞在套層發(fā)生分化。此時(shí)神經(jīng)管由內(nèi)向外由神經(jīng)上皮 層、套層和邊緣層（marginal layer）組成。 神經(jīng)嵴形成 來源于神經(jīng)嵴細(xì)胞的神經(jīng)組織 3. External signals Dorsal signals (e.g. BMP-4) and Ventral signal (Sonic hedgehog) pattern neural tube 神經(jīng)上皮形成中的有關(guān)信號(hào): BMP（Bone Morphogenetic Protein）蛋白家族成BMP-4在神經(jīng)誘導(dǎo)中起

45、 關(guān)鍵作用，其主要功能是：BMP4并不是直接作用于將形成神經(jīng)組織的細(xì)胞， 而是神經(jīng)組織形成的抑制物。 很多與BMP競爭的分泌蛋白，包括Chordin、Noggin、Cerberus都與神經(jīng) 誘導(dǎo)有關(guān): Chordin在將來的神經(jīng)板下面的組織的中胚層中表達(dá)，它可以與BMP-4結(jié)合， 抑制其活性。 Noggin，由組織者（中胚層、脊索）表達(dá)分泌。 Cerberus，可以與BMP-4結(jié)合而抑制后者的信號(hào)。 示例：Xenopus laevis(爪蟾) 遷移機(jī)制： 依賴于細(xì)胞間黏附因子（ cell adhesion molecule ）的表達(dá)： 曾經(jīng)是外胚層一部分的神經(jīng)管，在它形成之后從預(yù)期的表皮組織中

46、分開， 這涉及到細(xì)胞黏著的變化。 示例： 在雞胚(chicken embryo)中，神經(jīng)板細(xì)胞起初和外胚層的其余部分一 樣，在它們的表面表達(dá)相同的黏著因子L-CAM（cell adhesion molecule）。 但隨著發(fā)育的進(jìn)程，神經(jīng)板外胚層開始表達(dá)N-cadherin 和N-CAM， 而鄰近的外胚層只表達(dá)E- cadherin。這些黏著性的改變可能使神經(jīng)管從 周圍的外胚層分開。 Mechanism of neural migration in vertebrates Slug mediated-EMT（epithelial to mesenchymal transition ） 脊椎動(dòng)物

47、的神經(jīng)嵴細(xì)胞最初在神經(jīng)褶邊緣發(fā)生，當(dāng)神經(jīng)管閉合時(shí)， 它們經(jīng)歷了從表皮到間充質(zhì)細(xì)胞的轉(zhuǎn)換(EMT),離開中線上的表皮細(xì)胞層，從 兩側(cè)遷移離去。 從表皮到間充質(zhì)的轉(zhuǎn)變與slug基因有關(guān)，它參與調(diào)控從不移動(dòng)的上 皮細(xì)胞到可遷移的間充質(zhì)細(xì)胞的轉(zhuǎn)變過程。 slug基因在所有遷移的神經(jīng)嵴細(xì)胞中表達(dá)。對(duì)slug基因表達(dá)的抑制，將 阻礙細(xì)胞遷移。 Regulation of cadherin expression 遷移需要細(xì)胞與神經(jīng)管的黏著力的失去，在遷移發(fā)生的時(shí)，N- cadherin和E-cadherin從神經(jīng)嵴細(xì)胞中消失。 Role of Environmental signals 四、從干細(xì)胞看NS發(fā)

48、育 神經(jīng)干細(xì)胞（Neural stem cell, NSC)的概念： 始于20世紀(jì)90年代，是人們從成年個(gè)體腦內(nèi)分離培養(yǎng) 了能不斷分裂增殖且具有多種分化潛能的細(xì)胞群后提出的。 神經(jīng)干細(xì)胞的定義：具有分化為神經(jīng)元（neuron)、星形膠質(zhì) 細(xì)胞(astrocytes)和少突膠質(zhì)細(xì)胞oligodendrocyte)的能力， 能自我更新(self-renew)，并足以提供大量腦組織細(xì)胞的細(xì)胞 群。 1. The basic concept of neural stem cells Characteristics of neural stem cells（廣義的神經(jīng)干細(xì)胞 定義）： 1）可生成神經(jīng)組織

49、或來源于神經(jīng)系統(tǒng)，具有多向分化潛能 （Multilineage differentiation potential），包括跨胚層 分化； 2）能進(jìn)行自我復(fù)制與自我更新； 3）可通過不對(duì)稱分裂（ Asymmetric division ）產(chǎn)生一個(gè)新的 干細(xì)胞和一個(gè)祖細(xì)胞，對(duì)稱分裂(Symmetric division)則產(chǎn)生 兩個(gè)干細(xì)胞或兩個(gè)組細(xì)胞。 Neural stem cell marker（神經(jīng)干細(xì)胞的標(biāo)志物）： 1）Nestin(neuroepithelial stem cell protein, 巢蛋白) 屬于細(xì)胞內(nèi)的中間纖維蛋白，是神經(jīng)干細(xì)胞的標(biāo)志性抗原， 但巢蛋白的分布并不局限于

50、神經(jīng)干細(xì)胞。 2）CD133 神經(jīng)干細(xì)胞選擇性地表達(dá)CD133+/CD34-/CD45-, 以及CD9、 CD15、CD81和CD95等表面標(biāo)志物，其中CD133是神經(jīng)干細(xì) 胞特異的表面抗原，被用來分離和鑒定神經(jīng)干細(xì)胞。 2. 神經(jīng)系統(tǒng)是否起源于一種神經(jīng)干細(xì)胞？ 一般認(rèn)為神經(jīng)系統(tǒng)中干細(xì)胞的分化是通過潛能的逐步限制 而實(shí)現(xiàn)的：在周圍環(huán)境的控制下，多能神經(jīng)干細(xì)胞（原始神經(jīng)上 皮細(xì)胞）先產(chǎn)生各種前體細(xì)胞，爾后再形成相應(yīng)的成熟細(xì)胞。 神經(jīng)前體細(xì)胞： 神經(jīng)元限制性前體細(xì)胞（neuron-restricted precursor）; 膠質(zhì)限制性前體細(xì)胞（glia-restricted precursor）

51、; 神經(jīng)嵴干細(xì)胞（neural crest stem cell） 3. Adult neural stem cells（成體神經(jīng)干細(xì)胞） 傳統(tǒng)觀點(diǎn)認(rèn)為，中樞神經(jīng)系統(tǒng)的神經(jīng)元在出生后 不久就喪失其再生能力，成人腦組織一經(jīng)損傷就不能再 生。 近年的研究發(fā)現(xiàn)，在大多數(shù)成體哺乳動(dòng)物神經(jīng)系統(tǒng) 的側(cè)腦室壁的室管膜下區(qū)（subventricular zone, SVZ） 和海馬齒狀回的顆粒下區(qū)（hippocampal subgranular zone，SGZ）有神經(jīng)干細(xì)胞（neural stem cells， NSC）的存在。 1）成體神經(jīng)干細(xì)胞的來源： 在哺乳動(dòng)物(mammals )發(fā)育的原腸形成期 （gastrulation period，開始有神經(jīng)上皮細(xì)胞 （neuroepithelial cell