神经元的分化

1、1神经系统的发育孙丽荣南方医科大学南方医科大学 基础医学院基础医学院 神经生物学教研室神经生物学教研室2本图反应了胚胎神经系统的早期发育过程. a) 最初的胚胎中枢神经系统从薄层的外胚层开始发育.b)在神经系统发育中重要的第一步:神经沟的形成;c)神经沟壁,即神经褶向中靠拢并融合,形成神经管;d)随着神经管的生长,部分外胚层内陷到表层下,形成神经嵴,最后发育成外周神经系统.神经管神经嵴体节神经褶神经沟中胚层内胚层神经板复习3脑的分化脑的分化神神经经管管前脑前脑中脑中脑后脑后脑视泡视泡端脑泡端脑泡间脑间脑视神经、视网膜视神经、视网膜大脑皮层、白质、嗅球大脑皮层、白质、嗅球丘脑、下丘脑、脑室丘脑、

2、下丘脑、脑室顶盖顶盖-上丘、下丘上丘、下丘被盖被盖中脑水管中脑水管小脑小脑脑桥脑桥延髓延髓第四脑室第四脑室复习4大脑皮层的形态新皮层新皮层嗅皮层嗅皮层海马海马嗅裂嗅裂侧脑室侧脑室哺乳动物的三种皮层新皮层Neocortex，仅存于哺乳动物嗅皮层Olfactory cortex海马Hippocampus嗅裂Rhinal fissure侧脑室Lateral ventricle旧皮层或古皮层5皮层神经元都是呈层状排列的，而且绝大部分神经元胞体与脑的表面平行。分子层: 最靠近表面的神经细胞层, 由一层无神经元的组织将皮层与软脑膜分隔开。各层至少都有一层细胞，伸出大量的称为顶树突的树突，这些顶树突会伸入到

3、第一层，在那里形成众多的分叉。 大脑皮层的细胞结构 分子层Molecular layer软脑膜Pial surface顶树突Apical dentrite短吻鳄大鼠6发育过程中大脑皮层的改变71.神经细胞的增殖神经细胞的增殖 Neuronal proliferation2.神经细胞的迁移神经细胞的迁移 Neuronal migration3.神经细胞分化神经细胞分化 Neural differentiation4.轴突伸展轴突伸展 Axon guidance5.突触形成突触形成 Synaptogenesis6.神经细胞的死亡神经细胞的死亡 Neuronal death大脑皮层的形成8神经细胞的

4、增殖神经细胞的增殖 Neuronal Proliferation9MG1G2S神经细胞增殖的舞蹈表演神经细胞增殖的舞蹈表演室层边缘层脑室侧软膜侧囊泡壁250，000 per minute - 1011 neuronsOnly a few months10?11内因说内因说外因说外因说12G1 期的时程决定分裂方式期的时程决定分裂方式N, neuron; P, precursor cell.MCBA细胞命运决定因子细胞命运决定因子13转录因子决定细胞命运细胞命运的决定(cell fate determination) -Notch-1和numb蛋白的不均匀分布14不对称分裂决定细胞命运不对称分裂

5、决定细胞命运1 mother cell produces 10,000 daughter cells250，000/minute - 1011 neuronsOnly a few months?15神经细胞的迁移和分化神经细胞的迁移和分化Neuronal Migration and Proliferation163HthymidineDiI, DiO, hydrophilic dyeGFPNo label: C. elegansBromodeoxyuridine (BrDu) 细胞标记方法17特异性表达某种容易检测得到的基因18J.B. Angevine, et al. Nature 192:

6、766-768, 1961 注射注射: 妊娠妊娠11th, 13th, 15th, or 17th days 检测检测: 注射后注射后1 hr or 出生后出生后10th dayResults: Methods:Conclusion 1:皮层细胞主要来源于侧脑室室管膜。皮层细胞主要来源于侧脑室室管膜。注射后注射后1 hr检测检测: 细胞位于室管膜附近。细胞位于室管膜附近。神经细胞迁移的证据19Shown are entire anteroposterior extents of the cerebral cortex.15th d11th d13th d17th d1. Neurons mig

7、rate.2. Later generations of postmitotic neurons migrate out beyond earlier cellsConclusions20Inside-Out” Gradient of Cerebral Cortex Formation in the Rhesus Monkey21 - Inside-out较早分化的较大神经元先迁移并形成最内层，依次顺序向外；而较晚分化较早分化的较大神经元先迁移并形成最内层，依次顺序向外；而较晚分化的较小神经元则通过已形成的层次迁移并形成其外侧新的层次；的较小神经元则通过已形成的层次迁移并形成其外侧新的层次；不

8、论皮质不论皮质的什么区域，其最内层总是最早分化，而最外层则最后分化。的什么区域，其最内层总是最早分化，而最外层则最后分化。边缘层边缘层室层室层放射状胶质细胞放射状胶质细胞突起突起22r: rod cell 杆状双核细胞t: terminal of a rod cellbp: bipolar cell两极(神经)细胞mg： glial cell神经胶质细胞23Internal Timing Mechanism内在时间机制The time or the number of cell division Precursor cellsDevelopmental fate 24Community Mec

9、hanism环境作用机制Precursor cellsDevelopmental fate Inducible cues that change with time25神经元迁移的方式根据神经元迁移的方向：放射性迁移： radial migration 切线性迁移： tangential migration 26EM: Golgi-stained fetal macaque telencephalonRadial fibers extending from parent cell bodies to the pial surface,where they terminate in a char

10、acteristic endfoot.高尔基染色法高尔基染色法铬酸盐硝酸银染色法27Neurons migrate along radial glial cells to their final layers (3000 m mm)28radial-directed cortical neuronal migration放射状皮层神经细胞迁移migration:inside-firstoutside-lastBielas et al., 200429Radial glial cell division放射状神经胶质细胞分裂放射状神经胶质细胞分裂30神经细胞迁移和分化的认识过程31神经细胞迁移的

11、舞蹈表演32The arrows point to the tip of the leading process.Initial ventricle-directed;Subsequently towards the pial surface.33Two modes of radial migration放射性迁移的两种方式LocomotionMovement of the entire cell, including its leadingand trailing process, over considerable distancee.g., glial-guided radial mov

12、ement of neuronsTranslocationThe cell extends a leading process in the direction of migration, then moves the nucleus throughthe elongated process to its destination34A cell displaying somal translocation in an E14 cortical sliceNadarajah et al., 200135Translocating cells with branched, pial-directe

13、d processesNadarajah et al., 200136 a cell displaying presumptive glial-guided locomotion37Bielas, Annu. Rev. Cell Dev. Biol. 2004. 20:593618The two distinct forms of cortical neuron movement38Non-ratial/tangential migration切线性迁移切线性迁移39Major routes of tangential migration(1) MGE to the dorsal telenc

14、ephalon (2) CGE to dorsal telencephalon (3) Cortical-striatal boundary to the ventrolateral telencephalon (lateral cortical stream) (4) LGE to the olfactory bulb (rostral migratory stream).CGE, caudal ganglionic eminenceCTX, neocortexLGE, lateral ganglionic eminenceMGE, medial ganglionic eminenceOB,

15、 olfactory bulb40known and hypothesized routes of tangential cell migration(1) MGE to neocortex and hippocampus (2) MGE to LGE (3) corticalstriatal boundary to ventrolateral telencephalon (lateral cortical stream) (4) LGE to neocortex and hippocampus (5) CGE to dorsal telencephalon (6) LGE to olfact

16、ory bulb (rostral migratory stream) (7) Retrobulbar region to marginal zone41neurons from the medial ganglionic eminence (MGE) of the ventral telencephalon migrate toward the dorsal telencephalon. Initially, migration in the cortex is tangential but then becomes radial or oblique as neurons enter th

17、e cortical plate. 42Cell-cell interactionCell-ECM interaction43Defects in neuronal migrationBielas et al., 2004分子层44Position of cells born at specific developmental times is inverted in the adult reeler cerebral cortex45defects in neuronal migrationTissir and Goffinet, 200346The overall divisions of the cerebral wall are obvious in reeler. But the cortical plate is disorganized and cells are displaced by fibers that run obliquely in the cerebral wall. Many subplate cells are located with the Cajal-Retzius cells in a relatively cell-dense region known as the superplate (spp).Cortical pla