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1、Developmental BiologyChapter 5: Patterning the body plan in animals- -VertebratesPatterning the body plan in animals1 Development of the Drosophila body plan1.1 Specification of the antero-posterior and dorso-ventral axis in Drosophila oocyte1.2 Setting up the body axes in Drosophila1.3 Patterning t
2、he Drosophila embryo2 Patterning the vertebrate body plan2.1 Specification and setting up of the body axes in amphibians (Xenopus)2.2 Somite formation and antero-posterior patterning2.3 Patterning the vertebrate nervous system2.4 Specifying the left-right axis (left-right asymmetry of internal organ
3、s)All vertebrates, despite their many outward differences, have a similar basic body planThe skeleton of a mouse embryo illustrates the vertebrate body plan The AP axis: head, trunk with paired appendages (vertebral column脊柱) and the post-anal tailThe vertebral column is divided into cervical (neck)
4、, thoracic (chest), lumbar (lower back), and sacral (hip and lower) regionsThe DV axis: the mouth defining the ventral side and the spinal cord the dorsal sidePatterning the body plan in vertebratesn Early development in Drosophila is largely under the control of maternal factors that sequentially a
5、ctivate a different sets of the embryos own genes (zygotic genes) to pattern the body plan. n Vertebrate axes do not form from localized determinants, as in Drosophila. Rather, they arise progressively through a sequence of inductive interactions between neighboring cells. Amphibian axis formation i
6、s an example of this regulative development. n The experiments of Hans Spemann and his students showed there exists an embryonic organizer, Spemann organizer that determines the amphibian axis formation and patterns the embryo along the body axes through inducing such inductive interactions.Patterni
7、ng the body plan in animals1 Development of the Drosophila body plan1.1 Specification of the antero-posterior and dorso-ventral axis in Drosophila oocyte1.2 Setting up the body axes in Drosophila1.3 Patterning the Drosophila embryo2 Patterning the vertebrate body plan2.1 Specification and setting up
8、 of the body axes in amphibians (Xenopus)2.2 Somite formation and antero-posterior patterning2.3 Patterning the vertebrate nervous system2.4 Specifying the left-right axis (left-right asymmetry of internal organs)In the transplantation experiments, Hans Spemann and Hilde Mangold showed that the dors
9、al lip of the blastopore can induce the hosts ventral tissues to form a second embryo with clear antero-posterior and dorso-ventral body axes. Spemann refered the dorsal lip as the organizer.The discovery of the Spemann organizerDr Hans Spemann-the Nobel Laureate in Physiology or Medicine 1935For hi
10、s discovery of the organizer effect in embryonic developmentMechanisms underlying role of the Spemann organizer in development of the body plann How was the organizer specified and formed? What caused the dorsal blastopore lip to differ from any other region of the embryo?n What factors were being s
11、ecreted from the organizer to create the antero-posterior and dorso-ventral axes?n How did the patterning of the embryo along the body axes become accompanied?Mechanisms underlying role of the Spemann organizer in development of the body plann How was the organizer specified and formed? What caused
12、the dorsal blastopore lip to differ from any other region of the embryo?n What factors were being secreted from the organizer to create the antero-posterior and dorso-ventral axes?n How did the patterning of the embryo along the body axes become accompanied?The developmentally important maternal fac
13、tors are differentially localized along the animal-vegetal axis in the Xenopus unfertilized eggsThe Xenopus egg possesses a distinct animal-vegetal axis, with most of the developmentally important maternal products (mRNA/proteins) localized in the vegetal regionVg-1 is a member of TGF-beta family of
14、 signaling proteinsThe cortical rotation upon sperm entry can both specify the dorsal side of the amphibian embryo, and induce formation of the Spemann organizerThe cortical rotation relocates those maternal factors , such as Wnt-11 and Dishevelled protein originally located at the vegetal pole to a
15、 site approximately opposite to the sperm entry. These factors called dorsalizing factors specify their new location as the future dorsal side of the embryo, thus conferring the dorsal-ventral axisModel of the mechanism by which the Disheveled protein stabilizes beta-catenin in the dorsal portion of
16、 the amphibian eggThe role of Wnt pathway proteins in dorsal-ventral axis specification (I)E: Blocking the endogenous GSK-3 in the ventral cells of the early embryo leads to formation of a second set of body axisThe role of Wnt pathway proteins in dorsal-ventral axis specification (II)Model of the i
17、nduction of the Spemann organizer in the dorsal mesodermLocalization of stablized beta-catenin in the dorsal side of the embryoActivation of Wnt signaling activates genes encoding proteins such as SiamoisSiamois and TGF-beta signaling pathway function together to activate the goosecoid gene in the d
18、orsal portionGoosecoid as a transcription factor activates genes whose proteins are responsible for induction of the Spemann organizer in the dorsal mesodermn How was the organizer specified and formed? What caused the dorsal blastopore lip to differ from any other region of the embryo?n What factor
19、s were being secreted from the organizer to create the dorso-ventral and antero-posterior axes?n How did the patterning of the embryo along the body axes become accompanied?Mechanisms underlying role of the Spemann organizer in development of the body planThe functions of the Spemann organizer (I)n
20、The ability to self-differentiate dorsal mesoderm into prechordal plate, chordamesoderm (notochord脊索) etcn The ability to dorsalize the surrounding mesoderm into paraxial (somite-forming) mesoderm (When it would otherwise form ventral mesoderm)n The ability to dorsalize the ectoderm, inducing the fo
21、rmation of the neural tuben The ability to initiate the movements of gastrulation. Once the dorsal portion of the embryo is established, the movement of the involuting mesoderm establishes the AP axis. In Xenopus (and other vertebrates), the formation of the AP axis follows the formation of the DV a
22、xisThe functions of the Spemann organizer (II)n The Organizer functions in setting up the dorsal-ventral axis by secreting diffusible proteins (Noggin, chordin, and follistatin) that antagonize/block the BMP signal. These diffusible proteins generate a gradient of BMP signaling that specifies the DV
23、 axisn The Organizer is able to secret the Wnt blockers Cerberus, Dickkopf and Frzb in the anterior portion of the embryo that generate a gradient of Wnt signaling. Thus, the Wnt signaling gradient specifies the AP axis.The diffusible signal proteins secreted by the Spemann organizer (I)The Organize
24、r functions in setting up the dorsal-ventral axis by secreting diffusible proteins (Noggin, Chordin, and Follistatin) that antagonize/block the BMP signal. These diffusible proteins generate a gradient of BMP signaling that specifies the DV axisLocalization of noggin mRNA in the organizer tissueAt g
25、astrulation, noggin is expressed in the dorsal blastopore lipDuring convergent extension, noggin is expressed in the dorsal mesoderm (the notochord, prechordal plate etc )Noggin protein is important for development of the dorsal and anterior structures of the Xenopus embryoRescue of dorsal structure
26、s by Noggin proteinMost top: The embryo lacks dorsal structures due to exposure to the UVThe 2nd-4th panel: the rescued embryos with dorsal structures in a dosage-related fasion, when the defect embryo is injected with noggin mRNAThe bottom: If too much noggin mRNA is injected, the embryo produces d
27、orsal tissues at the expense of ventral and posterior tissue, becoming little more than a head.Model for the action of the Organizer in specifying the DV axisP-Smad1 antibody staining shows the gradient of the BMP signaling along the DV axis in an early gastrulating Xenopus embryoA gradient of BMP4
28、signaling elicits the expression of different genes in a concentration-dependent fasion The diffusible signal proteins secreted by the Spemann organizer (II)The Organizer is able to secret the Wnt blockers Cerberus, Dickkopf and Frzb in the anterior portion of the embryo that generate a gradient of
29、Wnt signaling. Thus, the Wnt signaling gradient specifies the AP axis.Cerberus, a secreted protein from the organizer is important for development of the most anterior head structuresInjection of Cerberus mRNA into a vegetal ventral Xenopus blastomere at the 32-cell stage induce ectopic head structu
30、resFrzb, another secreted protein from the organizer is important for development of the most anterior head structuresThe frzb is expressed in the head endomesoderm of the organizerThe frzb mRNA: dark blueThe chordin mRNA: brownMicroinjection of frzb mRNA into the marginal zone leads to the inhibiti
31、on of trunk formation, due to inactivation of the Wnt signalingThe organizer is able to secret different sets of signal proteins that antagonize/block BMP and (or) Wnt signalingMechanisms underlying role of the Spemann organizer in the body axis formationn How was the organizer specified and formed?
32、 What caused the dorsal blastopore lip to differ from any other region of the embryo?n What factors were being secreted from the organizer to create the antro-posterior and dorso-ventral axes?n How did the patterning of the embryo along the body axes become accompanied?The trunk mesoderm of a neurul
33、a-stage embryo can be subdivided into four regions along the dorso-ventral axis The trunk mesoderm of a neurula-stage embryo can be subdivided into four regions along the dorso-ventral axis Patterning the mesoderm along the dorso-ventral axis (subdivision of the mesoderm) is controlled by the gradie
34、nt of BMP4 signaling. High doses of BMP4 activate those genes (e.g, Xvent1) for development of the lateral plate mesoderm Intermediate levels of BMP4 instruct formation of the intermediate mesoderm Low doses of BMP4 regulate the paraxial mesoderm differentiation through activating myf5 et al The mes
35、oderm becomes notochord tissue when no BMP4 activity is present in the most dorsal region The antero-posterior axial patterning in vertebratesPatterning of the vertebrate embryo along the AP axis will be focused on:Patterning of the dorsal mesoderm that forms the somites, the blocks of mesodermal ce
36、lls that give rise to the skeleton and muscles of the trunkPatterning of the ectoderm that will develop into the nervous system. Patterning the body plan in animals1 Development of the Drosophila body plan1.1 Specification of the antero-posterior and dorso-ventral axis in Drosophila oocyte1.2 Settin
37、g up the body axes in Drosophila1.3 Patterning the Drosophila embryo2 Patterning the vertebrate body plan2.1 Specification and setting up of the body axes in amphibians (Xenopus)2.2 Somite formation and antero-posterior patterning2.3 Patterning the vertebrate nervous system2.4 Specifying the left-ri
38、ght axis (left-right asymmetry of internal organs)Neural tube and somites seen by scanning electron microscopyPatterning of the somite-forming mesoderm along the antero-posterior axisn Somites are blocks of mesodermal tissue that are formed after gastrulation. They forms sequentially in pairs on eit
39、her side of the notochord, starting at the anterior end of the embryo or head end. The somites give rise to the vertebrae, to the muscles of the trunk and limbs, and to the dermis of the skin.n Somites differentiate into particular axial structures depending on their position along the AP axis. The
40、anterior-most somites skullThose posterior to them cervical vertebraeMore posterior ones thoracic vertebrae with ribsn The pre-somatic mesoderm is patterned along its AP axis before somite formation begins during gastrulation.n The positional identity of the somites is specified by the combinatorial
41、 expression of genes of the Hox complexs along the AP axis, from the hindbrain to the posterior end, with the order of expression of these genes along the axis corresponding to their order in the cluster along the chromosomen Mutations or overexpression of a Hox gene results, in general, in localize
42、d defects in the region in which the gene is expressed, and cause homeotic transformations（同源异型转化同源异型转化）.Somites are formed in a well-defined order along the antero-posterior axisSpecification of the pre-somitic mesoderm by position along the antero-posterior axis has occurred before somite formatio
43、n begins during gastrulation Identity of somites along the antero-posterior axis is specified by Hox gene expression (I)n The Hox (Homeobox) genes of vertebrates encode a large group of gene regulatory proteins that all contain a similar DNA-binding region of around 60 amino acids known as the homeo
44、domain. The homeodomain is encoded by a DNA motif of around 180 base pairs termed the homeobox, a name that came originally from the fact that this gene family was discovered through mutations that produce a homeotic transformationa mutation in which one structure replaces another. For example, the
45、four-winged fly. n Hox genes that specify positional identity along the AP axis were originally identified in Drosophila and it turned out that related genes are involved in patterning the vertebrate axis Identity of somites along the antero-posterior axis is specified by Hox gene expression (II)n A
46、ll the Hox genes whose functions are known encode transcriptional factors. Most vertebrates have four separate clusters of Hox genes. n A particular feature of the Hox gene expression in both insects and vertebrates is that the genes in each cluster are expressed in a temporal and spatial order that
47、 reflects their order on the chromosome. That is-a spatial pattern of genes on a chromosome corresponds to a spatial expression pattern in the embryo (The order of the genes in each cluster from 3，to 5，in the DNA is the order in which they are expressed along the AP axis). n The overall pattern sugg
48、ests that the combination of Hox genes provides positional identity for each somite. In the cervical region, for example, each somite, and thus each vertebra, could be specified by a unique pattern of Hox gene expression Specification of the identity (characteristic strucutre) of each segment is acc
49、omplished by the homeotic selector (同源异型选择者同源异型选择者) geneslab and Dfd-the head segmentsScr and Antp- the thoracic segmentsUbx - the third thoracic segment AbdA and AbdB-the abdominal segmentsHomeotic gene expression in DrosophilaThere are 2 clusters of the homeotic genes encoding the Antennapedia and
50、 bithorax complexesLoss-of-function mutations in the Ultrabithorax gene can transform the 3rd thoracic segment into another 2nd thoracic segment, producing a four-winged fly Almost every region in the mesoderm along the antero-posterior axis is characterized by a particular set of expressed Hox gene
51、sPatterning the body plan in animals1 Development of the Drosophila body plan1.1 Specification of the antero-posterior and dorso-ventral axis in Drosophila oocyte1.2 Setting up the body axes in Drosophila1.3 Patterning the Drosophila embryo2 Patterning the vertebrate body plan2.1 Specification and s
52、etting up of the body axes in amphibians (Xenopus)2.2 Somite formation and antero-posterior patterning2.3 Patterning the vertebrate nervous system2.4 Specifying the left-right axis (left-right asymmetry of internal organs)The ectoderm lying along the dorsal midline of the embryo becomes specified as
53、 neuroectoderm, the neural plate, during gastrulationDuring the stage of neurulation, the neural plate forms the neural tube, which eventually differentiates into the central nervous systemRhombomere: 菱脑节Branchial arches: 鳃弓Patterning the nervous system along the AP axisn Hox genes are expressed in
54、the mouse embryo hindbrain in a well-defined pattern, which closely correlates with the segmental pattern. Thus, Hox gene expression may provide a molecular basis for the identities of both rhombomeres (菱脑节) and the neural crest at the different positions in the hindbrain.n Both gene mis-expression
55、or gene knock-outs in mice have alreadly shown that change in the Hox gene expression causes a partial or complete homeotic transformation of one segment into another in the hindbrain. Thus, the Hox genes determine patterning of the hindbrain region along the AP axisPatterning the nervous system alo
56、ng the AP axisn Hox genes are involved in patterning the hindbrain, but Hox gene expression can not be detected in the most anterior neural tissues of the mousethe midbrain and forebrain. n Instead, homeodomain transcriptional factors such as Otx and Emc are expressed anterior to the hindbrain and s
57、pecify pattern in the anterior brain in a manner similar to the Hox gene more posteriorly. In mice, Otx1 and Otx2 are expressed in overlapping domains in the developing forebrain and hindbrain, and mutations in Otx1 leads to brain abnormalities and epilepsy Patterning the body plan in animals1 Devel
58、opment of the Drosophila body plan1.1 Specification of the antero-posterior and dorso-ventral axis in Drosophila oocyte1.2 Setting up the body axes in Drosophila1.3 Patterning the Drosophila embryo2 Patterning the vertebrate body plan2.1 Specification and setting up of the body axes in amphibians (X
59、enopus)2.2 Somite formation and antero-posterior patterning2.3 Patterning the vertebrate nervous system2.4 The left-right asymmetry of the internal organsThe embryo has a left-right axis in vertebratesn In addition to its dorsal-ventral and anterior-posterior axes, the vertebrate embryo has a left-r
60、ight axis, that is, there are several internal organs, such as the heart and the gut tube, that are not evenly balanced on the right and left sides. n In all vertebrates studied so far, the crucial event in left-right axis formation is the expression of a nodal gene in the lateral plate mesoderm on
61、the left side of the embryo. In Xenopus, this gene is Xnr1 (Xenopus nodal-related 1). If this gene is ectopically expressed on the right-hand side, the position of the heart (which is normally on the left side) and the coiling of the gut are randomized. The embryo has a left-right axis in vertebrate
62、sn What determines the expression of Xnr1 solely on the left-hand side? In Xenopus, the fertilization-induced cytoplasmic rotationThe Vg1 protein, one of TGF-beta family members, expressed throughout the vegetal hemisphere of the Xenopus oocyte, seems to be processed into its active form on the left-hand side of the embryo n The pathway by which the Xnr1 protein instructs formation of the left-right asymmetry is unknown, but one of the key genes activated by Xnr1 appears to be pitx2. pitx2, one of key genes activated by Xnr1, regulates the left-right asymmetry in Xenopus
