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1、Developmental Biology,Chapter 6: Development of the vertebrate germ layers and organogenesis (I),Development of the vertebrate germ layers and organogenesis,1 Development of the vertebrate germ layers 1.1 Ectoderm 1.2 Paraxial and intermediate mesoderm 1.3 Lateral plate mesoderm and endoderm 2 Devel
2、opment of the nervous system 2.1 The specification of neural cell ( neuron or glial cell) identity 2.2 Migration of neurons and the guided outgrowth of axons toward their target cells 2.3 Synapse formation and refinement,3 The limb development 3.1 Formation of the limb bud and limb outgrowth 3.2 Gen
3、eration of the proximal-distal axis of the limb 3.3 Specification of the anterior-posterior limb axis 3.4 Generation of the dorsal-ventral axis 3.5 Coordinating the three axes 3.6 Development of the digits 4 Formation of internal organs, blood vessels, lungs, kindney, heart, and teeth (Option),Devel
4、opment of the vertebrate germ layers and organogenesis,Development of the vertebrate germ layers and organogenesis,1 Development of the vertebrate germ layers 1.1 Ectoderm 1.2 Paraxial and intermediate mesoderm 1.3 Lateral plate mesoderm and endoderm 2 Development of the nervous system 2.1 The speci
5、fication of neural cell ( neuron or glial cell) identity 2.2 Migration of neurons and the guided outgrowth of axons toward their target cells 2.3 Synapse formation and refinement,Major derivatives of the ectoderm germ layer,dorsal,ventral,Major derivatives of the ectoderm germ layer,dorsal,ventral,M
6、ajor derivatives of the mesoderm germ layer,The major function of the embryonic endoderm is to construct the linings of two tubes within the vertebrate body,The digestive tube and its derivatives (liver, gallbladder, and pancreas),The major function of the embryonic endoderm is to construct the lini
7、ngs of two tubes within the vertebrate body,The respiratory tube,The digestive tube and its derivatives (liver, gallbladder, and pancreas),Development of the germ layers and organogenesis,1 Development of the germ layers 1.1 Ectoderm 1.2 Paraxial and intermediate mesoderm 1.3 Lateral plate mesoderm
8、and endoderm 2 Development of the nervous system 2.1 The specification of neural cell ( neuron or glial cell) identity 2.2 Migration of neurons and the guided outgrowth of axons toward their target cells 2.3 Synapse formation and refinement,Development of the nervous system,The nervous system is the
9、 most complex of all the organ systems in the animal embryo. In mammals, for example, billions of nerve cells, or neurons, develop a highly organized pattern of connections, creating the neuronal network that makes up the functioning brain and the rest of the nervous system. The nervous system conta
10、ins many hundreds of different types of neurons, varying in sizes, shapes and functions. The nervous system can only function properly if the neurons are correctly connected to one another, thus a central question in nervous system development is how the connections between neurons with each other a
11、nd with other target cells develop with the appropriate specificity.,Development of the nervous system,Neurons connect with each other and with other target cells, such as muscle, at specilized junctions known as synapses（突触）. A neuron receives input from other neurons through its highly branched de
12、ndrites, and generate a nerve impulse at the cell body. This nerve impulse is then conducted along the axon to the axon terminal, which makes a synapse with the dendrites or cell body of another neuron or with the surface of a muscle cell. The dendrites and axon terminals of individual neurons can b
13、e extensively branched, and a single neuron in the CNS can receive as many as 100,000 different input.,Development of the nervous system,Development of the nervous system involve neuronal cell differentiation, morphogenesis, and migration The overall process of nervous-system development can be divi
14、ded up into four major stages: The specification of neural cell (neuron or glial cell) identity The migration of neurons and the outgrowth of axons to their targets The formation of synapses between neurons with each other and with other tragets, such as muscle etc The refinement of synaptic connect
15、ions through the elimination of axon branches and cell death,Development of the germ layers and organogenesis,1 Development of the germ layers 1.1 Ectoderm 1.2 Paraxial and intermediate mesoderm 1.3 Lateral plate mesoderm and endoderm 2 Development of the nervous system 2.1 The specification of neur
16、al cell ( neuron or glial cell) identity 2.2 Migration of neurons and the guided outgrowth of axons toward their target cells 2.3 Synapse formation and refinement,Development of the germ layers and organogenesis,1 Development of the germ layers 1.1 Ectoderm 1.2 Paraxial and intermediate mesoderm 1.3
17、 Lateral plate mesoderm and endoderm 2 Development of the nervous system 2.1 The specification of neural cell ( neuron or glial cell) identity 2.2 Migration of neurons and the guided outgrowth of axons toward their target cells 2.3 Synapse formation and refinement,The presumptive nervous system is s
18、pecified early in embryonic development in both invertebrates and vertebrates,The presumptive nervous system is specified early in embryonic development in both invertebrates and vertebrates,Specification of the neuronal precursors involves lateral inhibition in both invertebrates and vertebrates,In
19、 Drosophila, the neurectoderm is subdivided along the AP and DV axes into a precise orthogonal （直角） pattern of proneural clusters. Within each cluster, cell-cell interactions through lateral inhibition direct one cell into a neural precursor or neuroblast fate. The rest become epidermal cells. As in
20、 Drosophila, lateral inhibition specifies single cells as neuronal precursors in the vertebrate nervous system.,Further development of neurons from neuronal precursors involves asymmetric cell division in Drosophila,After specification, the Drosophila neuroblasts delaminate from the neurectodermal e
21、pithelium to lie adjacent to its inner, or basal face, and then behave as a stem cells. Each neuroblast divides asymmetrically to give an apical cell, which remains a neural stem cell, and a smaller basal cell, the ganglion mother cell (GMCs), which will differentiate into neurons.,The localized pro
22、tein determinants in neuroblasts specify the orientation of cell division and daughter cell fate: Numb: the ganglion mother cell fate Insc/Pins: the orientation of the plane of cell division Bazooka Prospero/Miranda Numb,The pattern of differentiation of cells along the DV axis of the spinal cord de
23、pends on ventral and dorsal signals,There is a distinct dorso-ventral pattern in the developing spinal cord. Specifically, different types of neurons differentiate along the DV axis. Motor neurons and interneurons are located ventrally, whereas commissural neurons （连合神经元）differentiate in the dorsal
24、region Differentiation of neuronal subtypes along the DV axis is determined by Sonic hedgehog protein (Shh), the ventral signal secreted by the notochord, and BMPs, the dorsal signal from the dorsal epidermal ectoderm,BMP signal,Shh signal,The neurons of the spinal cord are given their identity by e
25、xposure to the gradients of two signal proteins,The graded signal proteins cause different transcriptional factors to be activated in the nuclei of the neuronal cells, depending on their position along the DV axis,A graded Sonic hedgehog signal patterns different neuronal types in the ventral region
26、 of the spinal cord through regulating two classes of homeodomain protein genes,The distribution pattern of the signal proteins and homeodomain proteins in chick neural tube along the DV axis,BMPs,Shh,Pax7,Pax6,Nkx6.1,F: Chick neural tube G: In situ hybridization for 3 Homeodomain proteins. Where Nk
27、x6.1 and Pax6 overlap, the motor neurons become specified.,MNs,MNs,Development of the germ layers and organogenesis,1 Development of the germ layers 1.1 Ectoderm 1.2 Paraxial and intermediate mesoderm 1.3 Lateral plate mesoderm and endoderm 2 Development of the nervous system 2.1 The specification o
28、f neural cell ( neuron or glial cell) identity 2.2 Migration of neurons and the guided outgrowth of axons toward their target cells 2.3 Synapse formation and refinement,The developmental process for establishing the functioning network of neurons,Migration of immature neurons The migration of neural
29、 crest cells What controls the the neural crest migration? Outgrowth of axons toward their targets How is the growth of axons guided? What are the mechanisms underlying the axon guidance?,The functioning neuronal network involves both migration of immature neurons and outgrowth of axons toward their
30、 targets (I),Neural crest cells and axonal outgrowth of neurons share the property of having to migrate far from their source of origin to specific places in the embryo They both need to recognize cues (信号) to begin this migration, and respond to signals that guide them along specific routes to thei
31、r final destination Many of the signals recognized by neural crest cells and by axonal growth cones are the same,The functioning neuronal network involves both migration of immature neurons and outgrowth of axons toward their targets (II),The functioning neuronal network involves both migration of i
32、mmature neurons and outgrowth of axons toward their targets (I),Migration of immature neurons The migration of neural crest cells What controls the the neural crest migration? Outgrowth of axons toward their targets How is the growth of axons guided? What are the mechanisms underlying the axon guida
33、nce?,dorsal,ventral,The neural crest cells migrate extensively to generate a large number of differentiated cell types,The fate of the neural crest cells depends, to a large degree, on where they migrate to and settle,The neural crest can be divided into 4 main domains (overlapping), each with chara
34、cteristic derivatives and functions,The cranial (cephalic 头部) neural crest cells： The cartilage, bone, cranial neurons, glia and connective tissues of the face The trunk neural crest cells The dorsal root ganglia containing the sensory neurons The sympathetic ganglia, the adrenal medulla, melanocyte
35、s etc The vagal (neck) and sacral (骶) neural crest cells Parasympathetic ganglia of the gut The cardiac neural crest cells Melanocytes, neurons, cartilage, and connective tissues The entire muscular-connective tissue wall of the large arteries,Neural crest cell migration is controlled by environment
36、al cues and adhensive differences (I),The adhensive differences The dynamic expression of N-cadherin in neural crest cells is essential for the initiation of neural crest cells, the segragation of the neural crest cells from the neural tube. ( N-cadherin is expressed in neural crest cells prior to m
37、igration, and after migration. But, down-regulation of N-cadherin expression at the time of migration, and turning off of N- cadherin expression during migration) Constitutive expression of N-cadherin dramatically supresses the movement of the neural crest cells from the neural tube.,Neural crest ce
38、ll migration is controlled by environmental cues and adhensive differences (II),The environmental cues (cues from the extracellular matrices) Migration-promoting proteins : fibronectin (纤维连接蛋白), laminin (层粘连蛋白), various collagen molecules, and proteoglycans etc ( by binding to integrin in neural cre
39、st cells) Migration-impeding proteins : the ephrin proteins (by binding to Eph receptor in neural crest cell membranes),Ephrin functions as a repulsive signal for neural crest cell migration,A: Negative correlation between regions of the ephrin in the sclerotome生骨节 and the presence of neural crest c
40、ells B: When neural crest cells are plated on fibronectin-containing matrices with alternating stripes of ephrin, they bind to thoe regions lacking ephrin C: Composite scheme showing the migration of spinal cord neural crest cells and motor neurons through the ephrin-deficient anterior regions of th
41、e sclerotomes,The functioning neuronal network involves both migration of immature neurons and outgrowth of axons toward their targets (I),Migration of immature neurons The migration of neural crest cells What controls the the neural crest migration? Outgrowth of axons toward their targets How is th
42、e growth of axons guided? What are the mechanisms underlying the axon guidance?,The growth cone controls the path taken by the growing axon,Dendrites are the fine, branching extensions of the neuron that are used to pick up electric impulses from other cells. In human, the average cortical neuron co
43、nnects with 10,000 other neural cells. Axon is a continuous extension of the nerve cell body which may be several feet long. Neurons make functional connections with their targets through outgrowth of axons. The outgrowth of the axon is guided by the growth cone at the axon tip,The growth cone moves
44、 by the elongation and contraction of pointed filopodia called microspikes (微突). These microspikes contain actin microfilaments, which are oriented parallel to the long axis of the axon.,The growth cone controls the path taken by the growing axon,actin,tubulin,The growth cone both moves and senses i
45、ts environment, functioning as both locomotor and sensory apparatus,In general, the growth cone moves in the direction in which its filopodia make the most stable contacts with other cells and with the extracellular matrix. The extracellular signals can bind to receptors on the growth cone surface,
46、and influence its direction of migration. The extension and retraction of filopodia involves the assembly and disassembly of the actin cytoskeleton. Members of a family of intracellular signaling proteins, the Ras-related GTPases, are involved in the reorganization of the actin cytoskeleton: Activat
47、ion of Rho cause growth cones to stop extending Rac and Cdc42 are involved in growth-cone extension How growth cones transduce extracellular signals so as to extend or collapse filopodia is not fully understood.,The growth cone controls the path taken by the growing axon,Axon growth cones are guided
48、 by two main types of cueattractive and repulsive signals,Chemoattractant proteins Netrins Cadherins Chemorepellants proteins Semaphorins Ephrin Slit proteins These signal proteins often function as both attractants and repellants, depending on the cellular context,Axon growth cones are guided by tw
49、o main types of cue-attractive and repulsive,Netrin-1 is a key attractant produced in the floor plate and in the middleline,Motor neurons from the spinal cord make muscle specific connections controlled by EphA signaling,Development of the germ layers and organogenesis,1 Development of the germ layers 1.1 Ectoderm 1.2 Paraxial and intermediate mesoderm 1.3 Lateral plate mesoderm and endoderm 2 Development of the nervous system 2.1 The specification of neural cell ( neuron or glial cell) identity 2.2 Migration of neurons and the guided out