发育生物学体节和神经系统课件

1、 在原肠运动进行的过程中及之后一段时间内，脊椎动物的模式建成沿身体的前后轴和背腹轴进行。 Key morphogenetic events are the formation of the somites, which give rise to muscles, skeleton and dermis. 轴旁中胚层由紧邻脊索增殖较快的中胚层细胞形成纵列的细胞索，并很快横裂为左右成对的体节。体节共42-44对，分化为真皮、中轴骨骼及骨骼肌。 神经系统是背方外胚层由邻近组织，特别是组织者(organizer)区域发出的诱导形成的。体节是沿前后轴按照预定顺序形成的Growth factor FGF

2、and retinoic acid (RA) gradients help to pattern the antero-posterior axis in the mouse embryos An antero-posterior gradient of FGF develops in the embryo, with its high point at the node The somites are formed when the FGF levels drops to some low threshold. Retinoic acid secreted by the somites fo

3、rms an opposing gradient that antagonizes FGF.体节是沿前后轴按照预定顺序形成的 Somites differentiate into particular axial structures depending on their position along the antero-posterior axis: anterior-most skull, posterior-cervical vertebrae, more posterior-thoracic vertebrae with ribs. Position specification前后轴

4、上不同位置的体节的特性是由Hox基因特化的HOM-C基因的结构十分复杂，有的基因有多个启动子和多个转录起始位点。其另一个重要特征是都含有一段的保守序列，称为同源异型框(homeobox)。含有同源异型框的基因统称为同源异型框基因(homeobox gene)。由同源异型框编码的同源异型结构域(homeodomain) 可形成与DNA特异性结合的螺旋-转角-螺旋结构 (helix-turn-helix) 。HOM-C同源异型框形成与DNA特异结合的螺旋-转角-螺旋结构。前后轴上不同位置的体节的特性是由Hox基因特化的 Patterning along antero-posterior axis

5、involves the expression of a set of genes that specify positional identity or positional value along the axis. The Hox genes. In the mouse, 4 Hox complexes, designated Hoxa, b, c, d 果蝇HOM-C的表达使每一个体节被进一步特化， The homeobox genes are a widespread conservation of developmental genes in animalsModel for a

6、Hox gene cluster records positional identityGene activity can provide positional value. The model shows how the pattern of gene expression along a tissue can specify the distinct regions W,X,Y and Z. e.g., only gene I is expressed in region W but all four genes are expressed in region Z.Temporal and

7、 spatial colinearity: order of Hox genes in DNA follows the antero-posterior body axis. Why have Hox genes stayed together in a complex?Fig. 19RAREHox complexes have a retinoic acid receptor response element (RARE) in the DNA before paralogue 1. This DNA enhancer element controls expression of many

8、genes in the complex. In retinoic acid teratogenesis, Hox gene expression borders move into more anterior regions. Fig. 23The role of Hox genes can be studied by knock-outHox gene expression in the mouse embryo after neurulation The “anterior” genes are expressed first. In the mouse, 4 Hox complexes

9、, designated Hoxa,b,c,d As the posterior pattern develops late, clearly defined patterns of Hox gene expression are most easily seen in the mesoderm and the neural tube after somite formation and neurulation, respectively.Hox基因在小鼠体节中的表达 The patterns of Hox gene expression could specify the identity

10、of the tissues at different position For example, the pattern of expression is quite different in anterior and posterior regions of the body axis Patterns of Hox gene expression in the mesoderm of chick and mouse embryos, and their relation to regionalization Hoxd9 and Hoxd10 are expressed at the tr

11、ansition between lumbar and sacral regions, as Hoxc5/6 at the cervical and thoracic vertebral transition in both chick and mouse.敲除或过表达Hox 基因均可造成体轴模式建成的改变 Hoxa3 -/- : structural defects in the regions of the head and thorax; but more posterior axial structures, show no evident defects. Posterior dom

12、inance or posterior prevalence : more posteriorly expressed Hox genes tend to inhibit the action of the Hox genes normally expressed anterior to them. 敲除或过表达Hox 基因均可造成体轴模式建成的改变 Homeotic transformation: loss of Hox gene function results in the conversion of one body part into another. e.g., Hoxa8-/-

13、mice, the first lumbar vertebra is transformed into a rib-bearing thoracic vertebra. microRNA may be involved in post-transcriptional regulation of Hox gene expression.Hox基因缺陷导致肢体相应部位的缺失人的多指症也可能与Hox基因的异位表达有关神经管的形成 神经管(neural tube)是中枢神经系统的原基，其形成称为neurulation。其方式分primary neurulation和secondary neurulat

14、ion两种。 1. Primary neurulation: 由外胚层细胞增殖、内陷并最终离开外胚层表面而形成中空的神经管。绝大多数脊椎动物前部神经管的形成采用此种方式。 神经管形成的起始：来自背部中胚层的信号诱导预置神经板边缘的细胞的背测收缩，而预置的表皮细胞向中线移动，使表皮与神经板交接处凸起形成神经褶。 Primary neurulation的过程神经管形成的扫描电镜图 神经管与相邻外胚层细胞分离可能与细胞粘连分子有关神经管沿AP 轴线依次闭合，完成形成过程。 人类胚胎的神经管闭合缺陷症 不同区域的神经管的封口时间不同。第二区封口失败，胚胎的前脑不发育，即致死性的无脑症；第5区不封口导致

15、脊柱裂口症。 Sonic Hedgehog、Pax3等因子是神经管闭合所必需的。孕妇服用叶酸和适量的胆固醇可降低胎儿神经管缺陷的风险。Secondary Neurulation 特点：外胚层细胞下陷进入胚胎形成实心细胞索，然后在细胞索中心产生空洞形成中空的神经管。 鸟类、哺乳类、两栖类动物胚胎的后部神经管及鱼类胚胎的全部神经管的形成采取此种方式。斑马鱼神经管的形成 Organizer mesoderm 诱导神经管的形成两栖动物胚胎胚孔背唇诱导第二胚轴形成的作用叫做primary embryonic induction神经诱导作用组织者的作用及神经诱导：genes in the organize

16、r A similar pattern of gene activity in the 2 animals, with homologous genes being expressed. Goosecoid, is an early marker of the organizer that is expressed in the cells giving rise to foregut, pre-chordal plate and notochord; mimic almost all the properties of the organizer. 外胚层被诱导形成神经板 The nervo

17、us system is induced during gastrulation. The ventral tissue has not been determined at the time of transplantation, and the neural tissue is induced during gastrulation. 中胚层发出的信号造成神经系统模式建成 Induction of the nervous system by the mesoderm is region specific Mesoderm from different positions along the

18、 dorsal A-P axis of early neurulas induces structures specific to its region of origin; anterior mesoderm induce a head and brain; posterior mesoderm induces a trunk and tailModels of neural patterning by induction-two-signal model One signal from the mesoderm first induces anterior tissue throughou

19、t the whole ectoderm. A second, graded, signal from the mesoderm then specifies more posterior regions; Qualitatively different induces are localized in the mesoderm Posteriorizing signals: Wnt (frog, chick and Zebrafish), AVE (mouse)神经诱导作用的机制 组织中心产生的信号分子 (如Chordin、Noggin、Follistatin) 可拮抗腹部化信号 (如BMP

20、4)，从而使其附近的外胚层细胞朝预置的神经命运发育。 BMP4是最重要的上皮分化和腹侧化诱导因子。对于神经发生而言，它是抑制因子或抗神经化因子。四、神经元的分化神经元命运的确定lateral inhibition 跨膜蛋白Delta和Notch的相互作用在神经元命运确定中起关键作用。二者互作后，Notch通过一系列反应抑制NeuroD和Neurogenin的表达。Neurogenin是激活Delta表达所必需的。脊髓沿DV轴线的分化 脊髓沿背腹轴线的不同区域的细胞有不同的发育命运.脊髓沿DV轴分化的机制 腹部命运：决定于来自脊索和floor plate的信号。将脊索置于脊髓的侧面或背部，其接触

21、的脊髓部位将形成第二个floor plate, 附近分化出motor neuron, 但背部标志基因pax3和pax7的表达受抑制。 腹部信号分子是Sonic Hedgehog，其不同的浓度决定了不同的腹部命运(高浓度诱导motor neurons,而低浓度诱导 C. neurons)。 背部命运：决定于来自神经管形成中背部外胚层产生的BMP4和BMP7,它们能够诱导脊髓背部细胞表达BMP4和Dorsalin-1。 背、腹部信号分子间的互作提供了脊髓细胞分化的位置信息。如将notochord去除后，Dorsalin的表达区就向腹部扩展。SHH BMP4、BMP7 BMP4、BMP7 BMP4D

22、orsalin-1SHH 后脑的分区 脊椎动物后脑一般都再分出多个菱脑原节 (rhom-bomeres),每个菱脑原节是一个发育单位，节内的细胞可交换，而节间不能交换。 后脑产生控制面部和颈部的神经，其产生的神经嵴细胞分化出周边神经和面部骨骼和结缔组织。Hox基因在不同的后脑区域有不同的表达谱Hox基因为在发育中的后脑提供位置信息 在菱脑原节表达的转基因动物模型：Hoxb2的一个增强子使lacZ在r3和r5中表达；而Hoxb1的一个增强子使碱性磷酸酶在r4表达。Summary 体节是原肠运动后形成的由中胚层组织组成的块状结构，从胚胎的前端开始，体节在脊索两侧按顺序成对形成，发育成脊椎骨、躯干肌肉和真皮。 发育成体节的中胚层的区域性特性在体节形成前就已经特化。体节的位置特性是由Hox