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  5. Cell sociology and the problem of automation in the development of pluricellular animals

Scholz, S. Fischer, U. Luckenbach and D. Tran, A. Facciol, R. Lee, G. Jang, C. Byun, M. Jeun, P. Searson, K. BSR, MacRae and R. Beis and D. Kimmel, W. Ballard, S. Kimmel, B. Ullmann and T. Lammer, G. Carr, K. Wendler, J. Rawlings, S. Belanger and T. Postlethwait, Y. Yan, M. Gates, S. Horne, A. Amores, A. Milan, T. Peterson, J. Ruskin, R. Peterson, C. Hill, N. Mesens, M. Steemans, J. Xu and M. Kikuchi, J.

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Current Topics in Developmental Biology, Volume 51

Asnani and R. Pelster and W. Hu, D. Sedmera, H. Yost, E. Grant, V. Patterson, D. Grimes and R. Verkerk and C. One is a molecular machinery which starts at fertilization in the whole cytoplasm. It yields two programmes of differentiation, typically first an endodermal and then an ectodermal one.

The other component of the egg developmental programme, which does not require specific information, allows the interception of the first endodermal programme. The application of informatics to developmental automatism is discussed in the latter part of the paper. Unable to display preview. Download preview PDF. Skip to main content. Advertisement Hide.

Cell sociology and the problem of automation in the development of pluricellular animals. This process is experimental and the keywords may be updated as the learning algorithm improves. This is a preview of subscription content, log in to check access. Apter, M. Cybernetics and development. Google Scholar.

Wolpert Arbib, M. Automata theory in the context of theoretical embryology. Rosen, Ed. Ashby, W. Atlan, H. Auerbach, R. The organization and reorganization of embryonic cells. Beermann, W. Differentiation at the level of the chromosomes. Boon-Niermeijer, E. The effect of puromycin on the early cleavage cycles and morphogenesis of the Pond Snail Lymnaea stagnalis. Brachet, J. The biochemistry of development. Brandhorst, B. Two-dimensional gel patterns of protein synthesis before and after fertilization of sea-urchin eggs.

Brien, P. Blastogenesis and morphogenesis. Morphogenesis 7 , p. Chandebois, R. Cell sociology: a way of reconsidering the current concepts of morphogenesis. Cell sociology and the problem of position effect: pattern formation, origin and role of gradients. Counce, S. The causal analysis of insect embryogenesis. Waddington, Ed. Ede The effect on embryogenesis of a sex-linked femalesterility factor in Drosophila melanogaster. Czihak, G. Evidences for inductive properties of the micromeres RNA in seaurchin embryos. Kinetics of RNA synthesis in the cell stage of the sea-urchin Paracentrotus lividus.

Dalcq, A. A comparison of the various types of egg organization. Germ cells and Development, p. Dan, K. Modified cleavage pattern after suppression of one mitotic division. Cell Res. Dettlaff, T. Cell divisions, duration of interkinetic states of differentiation in early stages of embryonic development.

Ebert, J. Kaighn Keys to change factors regulating differentiation. When the vegetal region of an embryo is deleted just after fertilization, the embryo does not develop any dorsal identity. Vegetally deleted embryos can be rescued by injecting vegetal cytoplasm but not animal cytoplasm; again, this finding indicates the presence of a dorsalizing activity in the vegetal cytoplasm. The dorsalizing activity is present before oocyte maturation in prophase I oocytes Elinson and Pasceri, ; Holowacz and Elinson, , Exposure of prophase I oocytes to UV irradiation produces ventralized phenotypes even though cortical rotation has taken place.

In these embryos, no dorsalizing activity can be detected after cytoplasmic transplantation Elinson and Pasceri, This shows that dorsal determinants in the oocytes are destroyed by UV irradiation. UV irradiation of one-cell embryos also results in ventralized phenotypes, but the UV target is different from that in prophase I oocytes and is believed to be the microtubule array required for cortical rotation Elinson and Pasceri, Studies in ascidian embryos have demonstrated the existence of prelocalized ooplasmic factors in different regions of the fertilized eggs.

The animal, vegetal, and posterior regions of the embryo contain tissue-specific determinants for the development of epidermis, endoderm, and muscle, respectively Nishida, Blastomeres isolated from the posterior region of ascidian embryos develop autonomously to form muscle Deno et al. A search for localized maternal RNAs in ascidian embryos led to the identification of such RNAs specifically localized to the myoplasm Swalla and Jeffery, and ectoplasm Swalla and Jeffery, A maternal transcript, pem-3, has also been shown to localize to the posterior-vegetal cytoplasm of the egg after fertilization Satou, Etkin domains known as the KH-domain.

These findings provide a molecular basis for studying cytoplasmic determinants in ascidians. The possible existence of cytoplasmic determinants in mouse embryos is still being vigorously investigated Gardner, , It has been shown that embryos subject to centrifugation or mechanical mixing of cytoplasm develop normally Mulnard and Puissant, ; Evsikov et al.

This finding argues against specific localization of components in the cytoplasm. Deletions of different regions of a one-cell mouse embryo have no effect on normal development ZernickaGoetz, Again, this finding provides no evidence for there being early regional asymmetry in the mouse egg cytoplasm.

In addition, extensive cell mixing that occurs in the mouse epiblast prior to gastrulation is inconsistent with an early segregation of cell lineages by the inheritance of cytoplasmic determinants Beddington and Robertson, However, STAT3 and leptin have been shown to localize to the cortex of mouse and human oocytes, and potentially function to specify asymmetry during early cleavage Antczak and Van Blerkom, The alignment of the animal—vegetal axis of the mouse zygote with the axis of bilateral symmetry in blastocysts and the proximal—distal axis in egg cylinders suggests that some degree of regional specification or polarity might already exist in the egg cytoplasm Gardner, ; Weber et al.

Cortical Rotation A critical step in determining the prospective dorsal region of the embryo is triggered by cortical rotation. The mechanism and consequences of such movement has attracted considerable attention. An unfertilized Xenopus egg is radially symmetrical along the animal—vegetal axis. Upon fertilization, the dorsal—ventral axis is defined by the site of sperm entry in the animal region. The sperm entry site marks the future ventral side of the embryo and overlaps with the first cleavage plane, which divides the egg bilaterally into right and left halves.

In fact, axis-inducing activity has also been detected above the equatorial region in the animal dorsal sector Gallagher et al. A possible explanation for the apparent discrepancy between the degree of cortical rotation and the localization of dorsal activity comes from studies of microtubule-dependent movement in the vegetal cortical region Elinson and Rowning, ; Rowning et al. Early Xenopus Development 9 core Larabell et al. These multiple layers of microtubules align with the direction of rotation Elinson and Rowning, Since the rotation movement precedes the formation of the microtubule arrays, it has been suggested that the microtubules are not responsible for the rotation of the cortex Larabell et al.

However, small organelles can be propelled along the parallel array of microtubules that function independently of the cortex. Small organelles may therefore move along the microtubules by motor molecules toward the plus-end to the dorsal side of the embryo. Transport by microtubules thus accounts for the apparent differences in the localization of dorsalizing activity as predicted from the degree of rotation of the egg cortex. In keeping with the microtubule transport model, a downstream component of the Wnt pathway, Dishevelled Dsh , has been shown to associate with small vesicle-like organelles that are translocated to the prospective dorsal side by microtubules during cortical rotation Miller et al.

Microtubule transport is not only specific for dorsal—ventral specification in Xenopus embryos. A dynamic distribution of microtubules has also been observed in the yolk cells of zebrafish embryos Jesuthasan and Stahle, In zebrafish embryos, a set of parallel microtubules at the vegetal pole region is required for setting up initial asymmetry at the one-cell stage. At the eight-cell stage, microtubule tracks originating from the dorsal equatorial blastomeres extend toward the vegetal pole.

These microtubule tracks may function to mediate directional transport of organelles or determinants required for dorsal development. Nieuwkoop Center After cortical rotation takes place, it is thought that a signaling center—the Nieuwkoop center—is activated in the dorsal vegetal region that subsequently induces the formation of the organizer in the overlying cells in a non-cell-autonomous manner. In a series of tissue recombination experiments, different regions of the yolky vegetal mass of Urodele embryos were tested for their inductive capacity on animal caps Boterenbrood and Nieuwkoop, The dorsal vegetal region induced dorsal axial structures, whereas the lateral and ventral vegetal regions induced only ventral structures.

This tissue recombination assay has been referred to as the Nieuwkoop recombinant assay.

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The dorsal vegetal region carrying a dorsal endomesoderm-inducing property is commonly referred to as the Nieuwkoop center Gerhart et al. This region is a signaling center required for specifying the dorsal—ventral axis. The inductive effect of the dorsal vegetal cells is active between the early cleavage stage and the late blastula stage Boterenbrood and Nieuwkoop, Cell progenies from the Nieuwkoop center do not contribute to the dorsal lip or axial structures formed during gastrulation.

The progenies are located vegetal to the dorsal lip, in the endoderm, and are fated to become part of the anterior gut endoderm, as shown by lineage labeling Bauer et al. Etkin Vodicka and Gerhart, The proposed function of the Nieuwkoop center is to induce the cells immediately above in the equatorial region to form the organizer. However, the requirement of the dorsal vegetal cells for dorsal development has not been directly demonstrated by studies in which all tier C and tier D dorsal blastomeres are removed. In fact, all blastomeres in tier D can be removed without affecting axis formation Gimlich, Transplantations of cytoplasm, cortical peels, and blastomeres have demonstrated that dorsalizing activity is distributed broadly on the dorsal sector of the embryo, with the highest activities around the vegetal and equatorial regions before and after cortical rotation Kageura, ; Yuge et al.

Thus, the Nieuwkoop center may overlap physically with the region where the prospective organizer forms. Studies of axis induction by transplantation of blastomeres from cell embryos showed that both tier C and tier D dorsal blastomeres are active in the induction assay Gimlich and Gerhart, ; Gimlich, ; Kageura, The dorsalizing activity of tier C dorsal blastomeres and their participation in organizer formation during normal development also support the idea that the region that produces the early dorsal inductive signal overlaps with the organizer.

In summary, the Nieuwkoop center is an important concept in defining early inductive signaling during dorsal—ventral specification. The Nieuwkoop center has been regarded as a physical entity spatially and temporally distinct from the gastrula organizer. However, it is also possible that the cytoplasmic dorsal determinants, after translocation to the dorsal side by cortical rotation and interaction with components in the dorsal region, activate the Nieuwkoop center at the dorsal equatorial region during cleavage stage Kodjabachian and Lemaire, ; Moon and Kimelman, The Nieuwkoop center in turn directly induces formation of the organizer at the equatorial region during the blastula stage Kodjabachian and Lemaire, ; Moon and Kimelman, In this model, the Nieuwkoop center and the organizer essentially occupy the same region in the embryo but remain temporally distinct.

Molecular analysis of the Nieuwkoop center will help to clearly define its role in inducing the formation of the gastrula organizer. Siamois Lemaire et al. Siamois can be activated directly by Xwnt-8 and also by vegetal cortical cytoplasm Carnac et al. On the other hand, Xwnt-8 is not maternally expressed and cannot be the maternal dorsal determinant. Endogenous Xwnt-8 is expressed in the ventral—lateral marginal zone after the MBT and is involved in a Wnt pathway required for patterning of the mesoderm Christian and Moon, ; Hoppler et al.

The basic components of the Wnt pathway are largely conserved between different developmental processes found in C. The wingless pathway involved in epidermal cell differentiation in Drosophila has been characterized Klingensmith and Nusse, ; Siegfried and Perrimon, and provides a basis for study of the Wnt pathway in other systems. In contrast, when a secreted Wnt molecule is recognized by a transmembrane receptor of the frizzled family, a cytoplasmic component, Dsh, is activated. Etkin Figure 1 Components of the Wnt signaling pathway.

Early Xenopus Development 13 transactivation domain, but no nuclear localization signal. Tcf-1, -3, and -4 and Lef1 have been identified in both mouse and human. XTcf3 is the only frog homolog identified so far Molenaar et al. Tcf proteins also contain a HMG domain that recognizes a DNA consensus sequence within the regulatory sequence of target genes. Groucho and CBP are corepressors that associate with Tcf proteins to repress transcription van de Wetering et al.

Groucho has been suggested to function with a histone deacetylase complex to regulate histone acetylation on chromatin Choi et al.

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In Drosophila, dCBP lowers the affinity of armadillo to dTcf by the acetylation of a conserved lysine residue in the armadillo-binding domain Waltzer and Bienz, Tcf-3 and Tcf-4 contain two conserved sites at the C terminus for the binding of C-terminal binding protein, which is also involved in transcriptional repression. Studies with antimorphic protein have shown that the Xenopus homolog of C-terminal binding protein is involved in the regulation of dorsoanterior development Brannon et al.

The Tcf proteins have been proposed to be architectual factors controlling chromatin structure and transcription van Houte et al. The Tcf binding sites in the siamois promoter are required for the activation of siamois expression in the 14 Agnes P. Etkin dorsal region Brannon et al. They are also necessary for the repression of siamois expression on the ventral side of the embryo, since removal of Tcf binding sites from the siamois regulatory sequence results in ectopic expression in the ventral side of the embryo Brannon et al.

Mice deficient in both Tcf1 and Lef1 show defects in the formation of axial structures Galceran et al. Overexpression of a membrane-tethered form or a wild-type cytoplasmic form of plakaglobin can result in axis duplication Merriam et al. Activation of the Wnt pathway suppresses the activity of Xgsk-3 and results 1.

Overexpression of wild-type Xgsk-3 on the dorsal side of the embryo suppresses Wnt signaling and inhibits endogenous axis formation He et al. Two distinct modes of Xgsk-3 regulation have been reported Dominguez and Green, It is shown that an endogenous mechanism exists on the dorsal side of Xenopus embryos to deplete Xgsk-3 protein. A second mode of regulation occurs as a consequence of Wnt or Dsh expression, which causes a reduction in Xgsk-3 activity rather than depletion. APC was originally identified as a tumor suppressor gene because loss of APC function was observed in colon cancer Polakis, A mouse mutation, fused, produces a truncated gene product of axin Zeng et al.

Mutant embryos exhibit duplicate axis formation implicating Axin as a negative regulator of axis formation. Etkin ventralization of endogenous axis by axin. The presence of an RGS domain suggests a possible involvement of G proteins in the regulation of the Wnt pathway. Antisense oligonucleotide knockout experiments have demonstrated that GBP is required for the establishment of the dorsal—ventral axis in Xenopus embryos Yost et al.

Evidence indicates that GBP can also induce depletion Xgsk-3 proteins, similar to the endogenous activity existed on the dorsal side of the embryo Dominguez and Green, It appears that GBP is a regulator of Wnt signaling but is not a linear component of the pathway. CKI has been shown to phosphorylate Dsh. It has been suggested that such phosphorylation is not required for the functioning of CKI. Further studies on the regulation of Dsh by these two kinases will be required to determine their roles in transducing the Wnt signal.

Early Xenopus Development 17 8. Dsh is phosphorylated by active Wnt signaling Yanagawa et al. Dsh has been shown to translocate from the vegetal pole toward the prospective dorsal side Miller et al. However, depletion of the maternal gene products will be required to provide definitive evidence for a role of Dsh in the establishment of dorsal—ventral axis in Xenopus.

Frizzled Frizzled proteins are receptors for Wnt ligands Bhanot et al. Members of the Frizzled family contain a cysteine-rich domain, seven transmembrane domains, and sometimes a PDZ-binding domain. Overexpression of Xfrizzled-8 Xfz8 alone on the ventral side of an embryo induces a secondary axis in the absence of exogenously supplied Wnt ligands Deardorff et al. However, since the endogenous expression of Xfz8 is zygotically activated in the organizer region during gastrulation, Xfz8 is unlikely to function as the endogenous Wnt receptor for the dorsal specification pathway during the early cleavage of Xenopus embryos.

A maternally encoded frizzled protein, Xfz7, has recently been isolated Sumanas et al. Embryos depleted of Xfz7 mRNA are deficient in dorsal mesoderm formation. This study provides experimental evidence for the functioning of the Frizzled proteins upstream of other components of the Wnt pathway in dorsalventral mesoderm specification. Several Wnt ligands have been studied, and these can be divided into two classes according to their axis-inducing ability.

In contrast, Xwnt-4 Du et al. However, the Wnt molecules that have strong axis-inducing activity 18 Agnes P. Etkin are not expressed at the right time and right place to be the dorsalizing signal Moon and Kimelman, Overexpression of Xwnt-8 can induce a complete secondary axis, but endogenous expression is not detected until after the MBT in the ventral-lateral mesoderm. Although Xwnt-8b is maternally expressed and has strong-axis-inducing activity, it is localized to the animal region of cleavage-stage embryos Cui et al. Xwnt mRNA is localized to the vegetal cortex of the oocyte Kloc and Etkin, and the protein is differentially translated along the dorsal—ventral axis Schroeder et al.

This result demonstrates the divergence of signal transduction cascades that Wnt molecules can elicit. Treatment of embryos with lithium chloride during early cleavage stage produces a dorsalized phenotype. It was originally suggested that the dorsalizing effect of lithium is due to an activation of the phosphatidylinositol cycle Maslanski et al. A dominant negative form of dsh, Xdd1, although 1.

Early Xenopus Development 19 able to block ectopic axis formation by the activation of Wnt signaling, has no effect on endogenous axis formation Sokol, Similar results have been obtained for Wnt molecules in dominant negative forms Hoppler et al. Evidence supporting this model came from the study in which Dsh is shown to translocate from the vegetal pole toward the prospective dorsal side Miller et al. However, the possibility that translocation of dsh toward the future dorsal side is preceded by the signaling of a Wnt ligand at the vegetal cortex of the egg should not be ruled out.

The effect of Xdd1 overexpression has also been examined in prospective ectoderm transplanted with VCC Marikawa and Elinson, In keeping with the findings in embryos, overexpression of Xdd1 in prospective ectoderm has no effect on the activity of VCC, as demonstrated by the expression of target genes siamois and Xnr3. Overexpression of different components of the Wnt pathway has shown that the activity of VCC is not inhibited by Xdd1 or Xgsk-3 but is inhibited by Axin.

On the basis of these findings, it has been proposed that VCC may in fact act on Axin instead of Xgsk-3 to mediate its dorsalizing activity. Furthermore, transplantation of vegetal cortical cytoplasm, or overexpression of siamois, only induces ectopic axis formation when the recipient site is the equatorial region but not when the recipient site is the animal region Kageura, Overexpression of Vg1 alone induces dorsal mesoderm but no notochord, and Xwnt-8b alone does not induce mesoderm formation. Etkin response elements are present in the promoter of the organizer gene gsc.

For dorsal development to occur, the endogenous ligand has to be active in the embryo at the right time and place. Spatial restriction of Vg1 mRNA to the vegetal cortex is suggested to provide a localized source of maternal protein to act as a dorsal inducer Thomsen and Melton, Overexpression of a mutant form of Vg1 cannot perturb axis formation, although dorsal mesoderm and endoderm formation are affected Joseph and Melton, This finding indicates that Vg1 is required for dorsal development, but expression of Vg1 alone is not sufficient in specifying formation of the dorsal—ventral axis.

The use of a specifically designed dominant negative activin type II receptor, containing only the extracellular domain and lacking the transmembrane domain and intracellular domain, has circumvented the problem of nonspecific interference with other receptors at the cell surface Dyson and Gurdon, This dominant negative receptor selectively blocks the function of activin but not that of Vg1 and nodal-related factors Xnr1 and Xnr2, although BMP signaling is slightly inhibited.

Overexpression of this dominant negative activin type II receptor in Xenopus embryos has demonstrated the requirement of activin for the development of dorsal structures and the initiation of mesoderm induction. Furthermore, although knockout mice deficient in different activin subunits also show no defects in early development Matzuk et al. The signal is transduced from the activated type I receptors by Smad proteins, which shuttle between the cytoplasm and the 1.

The signal is transduced by the R-Smad, which is activated by the type I receptor. The R-Smad associates with a co-Smad and translocates into the nucleus. The R-Smad and co-Smad complex with additional transcriptional factors to activate expression of target genes such as mix2 and gsc. Several Smads function as transcription factors. Three classes of Smad proteins have been identified Christian and Nakayama, Receptor Smads R-Smads are phosphorylated by the intracellular domain of type I receptor.

The activated R-Smads escort a second class of Smads, the coactivator Smads co-Smads , into the nucleus to control target gene expression. The third class of Smads, the inhibitory Smads, prevent the R-Smads from binding to the type I receptor or the co-Smads. The activity of Smad proteins is under constitutive inhibition by interaction between the MH1 and MH2 domains Hata et al.

Such autoinhibition is released by the phosphorylation of the MH2 domain at a C-terminal motif of R-Smads. Etkin proteins Baker and Harland, ; Liu et al. Smad4 is a co-Smad Lagna et al. Smurf1, a ubiquitin ligase, can interact with and trigger ubiquitination and consequently the inactivation of Smad proteins specific for the BMP pathway Zhu et al. This finding suggests that FAST-1 is a key maternal regulator of transcriptional responses to mesoderm inducers Watanabe and Whitman, The Spemann Organizer In amphibians, the organizer forms at the dorsal lip of the blastopore of the gastrula embryo.

The organizer is known as the Spemann organizer because the axisinducing activity of this region was demonstrated for the first time in using urodelean amphibians by Hilda Mangold, a student of Hans Spemann Hamburger, Mangold transplanted dorsal blastoporal lips of advanced gastrulae of unpigmented newts to the flanks of pigmented host newts at the same stage of development Spemann and Mangold, In the most successful case, the 1.

Early Xenopus Development 23 resulting embryo had a secondary body axis containing anterior structures that included hindbrain and otic vesicles. In the secondary axis, the neural tube was composed entirely of cells that originated from the pigmented host embryo; the notochord contained cells that originated from the unpigmented transplanted tissue; and the somites were derived from a mixture of cells from both origins.

The ability of the transplanted dorsal blastoporal lip to recruit cells from the host embryo to participate in the formation of the secondary axis demonstrated that the transplaned tissue had an organizing ability. The inability of the dorsal lip of advanced gastrula to generate a complete secondary axis including the head prompted Spemann to test the hypothesis that the head and trunk were induced by different regions of the mesodermal tissue of the organizer.

Since the organizer is a highly dynamic structure and cells at the blastoporal lip continously undergo involution, the cell population at the blastoporal lip is distinct during different stages of gastrulation. These cells assume a progressively more posterior identity as gastrulation proceeds. By transplanting dorsal lip tissues to the ventral side of the blastocoel, Spemann demonstrated that blastoporal lip from the early gastrula induced head and brain structures while blastoporal lip from the late gastrula induced spinal cord and tail structures.

Regional specification of organizer-derived tissue was further demonstrated by Otto Mangold Mangold, Mangold showed that, at the neurula stage, the organizer-derived mesodermal tissue layer had assumed an anteroposterior identity and could be divided into regions including the anterior endomesoderm, the prechordal mesoderm, and the anterior and posterior chordamesoderm.

Of these, only the prechordal mesoderm, fated to form the head mesenchyme, demonstrated head-inducing ability. The anterior endomesoderm, the most anterior region containing cells of endodermal and mesodermal origins and fated to give rise to the liver, showed little or no head-inducing activity. The anterior region of the chordamesoderm gave rise to the hindbrain and spinal cord, whereas the posterior region of the chordamesoderm formed only the spinal cord.

Molecular characterization of the organizer has led to the identification of genes that are specifically expressed in the organizer and can induce secondary axes by acetopic expression. These organizer genes can be classified into three groups on the basis of the type of secondary axis generated. However, it should be noted that the organizer tissue is a dynamic structure.

The organizer is not a constant population of cells, and considerable cell movement and rearrangement take place during gastrulation. The products of some of these genes can induce 24 Agnes P. Etkin Figure 3 Expression domains of organizer genes in the head and trunk organizers. The organizer consists of four expression domains: anterior endomesoderm, prechordal mesoderm, superficial layer, and chordamesoderm. The head organizer is made up of the prechordal mesoderm and anterior endomesoderm.

The chordamesoderm possesses trunk organizer activity. The second group of organizer genes are expressed in the prechordal mesoderm region of the head organizer at the gastrula stage and can generate ectopically incomplete secondary axes lacking anterior structures.

The last group of organizer genes are expressed in the anterior endomesoderm of the head organizer at the gastrula stage.

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The product of some of these genes can produce an ectopic head without a trunk by overexpression. The expression domains of the organizer genes at the gastrula stage are summarized in Fig. Overexpression of either siamois or twin induces ectopic secondary axis with a complete head Lemaire et al. Vegetal cortical cytoplasm can induce siamois expression ectopically, indicating that siamois is a downstream target of the dorsal determinant in the vegetal cortical cytoplasm Darras et al. Transplantation of vegetal cortical cytoplasm to the animal hemisphere activates the expression of chordin, whereas transplantation of vegetal cortical 1.


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Early Xenopus Development 25 cytoplasm to the vegetal hemisphere activates the expression of cer. This shows that different regions along the animal—vegetal axis have diferent abilities to respond to the cytoplasmic dorsal determinant. Activation of cer expression in the vegetal hemisphere by siamois induces the formation of anterior endomesoderm, whereas the activation of chordin in the animal hemisphere induces the formation of the head organizer Darras et al.

Since overexpression of siamois mRNA in either the ventral vegetal region or the equatorial region results in ectopic axis formation Laurent et al. Like Siamois, Twin has been shown to bind to and activate the Wnt-responsive regulatory elements of the gsc promoter Laurent et al. The dorsal yolk syncytial layer forms at the blastula stage when cells in the deep marginal blastoderm release their nuclei into the yolk cells.

Organizer Genes Expressed in the Prechordal Mesoderm Organizer genes expressed in the prechordal mesoderm include genes that code for transcription factors Gsc, Xlim-1, Xanf-1, Xotx2 , growth factor antagonists noggin, chordin, follistatin, frzb, dickkopf-1 [dkk-1] , and growth factors Xnr14 and anti-dorsalizing morphogenetic protein [ADMP]. Most of these genes are expressed above the dorsal lip in the prechordal mesoderm, which contributes to the head mesenchyme.

Xnr-3 is most strongly expressed in the superficial layer of the dorsal lip, which gives rise to the pharyngeal endoderm. Overexpression of ADMP inhibits dorsal mesodermal markers, including organizer genes, and induces ventral markers Moos et al. Since the function of ADMP cannot be blocked by a dominant-negative BMP receptor or other BMP antagonists except follistatin, it may function in the trunk organizer to antagonize head formation by a distinct pathway Dosch and Niehrs, Etkin 1.

Genes Encoding Transcription Factors The transcription factor Gsc contains a paired class homeodomain and is able to generate an incomplete secondary embryonic axis when overexpressed Cho et al. Dissociated Xenopus embryos express the same level of gsc as undissociated embryos, indicating that the expression of gsc is cell autonomous—that is, independent of cell—cell interaction Lemaire and Gurdon, Analysis of isolated organizer explants has demonstrated that by the early gastrula stage, gsc expression is already limited to a discrete region of the organizer Zoltewicz and Gerhart, The gsc expression domain is spatially distinct from the Xnot expression domain in the posterior half, which normally gives rise to the chordamesoderm.

In the mouse, gsc is expressed in the anterior primitive streak and the anterior mesoderm, which gives rise to the head process Blum et al. However, the neural-inducing strength of the mouse node from gsc knockout mice is impaired, as demonstrated by studies in which gsc-deficient mouse node was transplanted to chick embryos Zhu et al. The presence of gsc-related genes in different systems, including Drosophila Goriely et al. A hydra homolog of gsc, Cngsc, has also been identified Broun et al. Cngsc is expressed in tissues with organizer activity and is able to induce a secondary axis when expressed in Xenopus embryos.

This suggests that the function of the Gsc protein has been conserved during evolution. In Xenopus, the requirement of gsc function has been demonstrated by studies involving overexpression of antimorphic forms of gsc, containing transcription activation domain or multiple copies of the myc epitope at the N terminus Ferreiro et al. The transcriptional activation effect of the myc epitope is not expected, and caution should be taken when the myc epitope is used in the context of a putative transcription factor Ferreiro et al. Antimorphic gsc is expected to inhibit the function of endogenous Gsc as well as other closely related family members, if they do exist in Xenopus.

When antimorphic gsc is expressed on the dorsal side of the embryo, ventral genes are activated ectopically, and embryos exhibit dorsoanterior defects. This finding shows that Gsc normally acts as a transcriptional repressor inhibiting ventral gene expression in the organizer region, and is consistent with the suggestion that Gsc functions as a transcriptional repressor to directly suppress the transcription of Xbra Artinger et al. Overexpression of antimorphic Gsc also activates expression of endogenous gsc, indicating a possible self-repression of gsc in embryos.

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Early Xenopus Development 27 axis lacking anterior structures when these genes are overexpressed in embryos. In addition, Xotx2 induces ectopic cement gland formation in embryos Blitz and Cho, ; Pannese et al. Mice deficient in lim1 have anterior truncations, including a missing forebrain and midbrain Shawlot and Behringer, A study of otx2 knockout mice demonstrated a loss of anterior neural structures in these animals Ang et al.

Gain-of-function studies in frogs and loss-of-function studies in mice together suggest an important role of Xlim-1, Xanf-1, and Xotx2 in development of the most anterior part of the head. When these genes are ectopically expressed on the ventral side of frog embryos, a secondary axis with an incomplete anterior structure is generated. The protein products of these genes are structurally distinct and have been shown to function through their ability to antagonize, and thus inhibit, BMP signaling by direct binding to BMP molecules.

Noggin is a glycoprotein secreted as a homodimer. Mouse noggin McMahon et al. This suggests that although noggin is not required for neural induction, it is important for later events, including patterning of somites and neural tube. Three noggin genes have been isolated from zebrafish Furthauer et al.

Although only a single noggin gene has been reported so far in other species, the finding of multiple noggin genes in zebrafish suggests that the functional redundancy of related genes should be taken into consideration. Chordin contains cysteine-rich domains CRs and is also secreted. The CRs have been shown to be novel protein modules for BMP binding and therefore confer the biological activity of chordin Larrain et al.

The zebrafish chordino mutant, originally known as dino, displays a partially ventralized phenotype with reduced head formation and, often, lacks a notochord, indicating an effect of chordin in organizer function Hammerschmidt et al. It is therefore informative to study mice deficient in either chordin or noggin or both of the genes to determine their requirement in specifying anterior development and a possible functional redundancy of these genes during early development. Double-homozygous mutant mice for chordin and noggin have been generated Bachiller et al.

These 28 Agnes P. Etkin embryos showed severe defects in the development of the forebrain. Chordin and Noggin are indeed required for anterior development in the mouse. BMP signaling has been shown to play a role in embryonic patterning Dale and Jones, Inhibition of BMP signaling by a cleavage mutant generates secondary axes Hawley et al. Chordin and Noggin have been shown to mediate a dorsalizing or axis-inducing effect by binding to BMPs and inhibiting BMP signaling in the organizer Holley et al. An additional level of regulation of BMP signaling is carried out by a metalloprotease of the astacin family Dumermuth et al.

Genetic studies in Drosophila have shown that tolloid can potentiate the effects of Dpp Shimell et al. The CUB domains may be required for protein—protein interaction—for example, to interact with the substrate. Xolloid has been demonstrated to cleave Chordin within specific sites. This suggests that Xolloid can negate the inhibitory effects of chordin on BMP signaling.

In Xenopus embryos, overexpression of Xolloid and XBMP-1 results in a ventralized phenotype as expected from the removal of Chordin from the embryo. Dominant negative forms of Xolloid and XBMP-1 produce embryos with a dorsalized phenoptype with enlarged heads and anterior structures, although the deletion mutant inhibits the activities of both Xolloid and XBMP In zebrafish, Xolloid is encoded by the mini fin mfn gene Connors et al.

In wild-type embryos, the presence of Mfn may negatively regulate Chordin activity and promote BMP signaling in the ventral marginal cells. A related sea-urchin metalloprotease, SpAN, when expressed in Xenopus embryos, can block the dorsalizing activity of both noggin and chordin 1. Early Xenopus Development 29 Wardle et al. The mechanism by which SpAN inactivates the dorsalizing function of noggin and chordin has yet to be determined. Follistatin was originally suggested to bind Activin directly and thereby control the amount of free Activin Tashiro et al.

The organizer function of Follistatin is further complicated by the fact that follistatin is not expressed in the equivalent of the organizer in zebrafish Bauer et al. In addition, no axial defects are detected in follistatin knockout mice Matzuk et al. This result argues against a requirement for follistatin during early development. The role of follistatin in the inhibition of BMP signaling and organizer activity requires further investigation. The expression pattern of frzb1 is complementary to endogenous Xwnt-8 expression in the ventral lateral mesoderm. Frzb functions as a growth factor antagonist by direct binding to Wnts and thus inhibition of Wnt signaling.

Frzb belongs to a clas of proteins that are known as frizzled-related proteins FRPs because their structure is similar to that of the membrane-bound Wnt receptor of the frizzled family, except that FRPs lack the transmembrane domain. Overexpression of frzb generates a partial secondary axis at a low frequency, and overexpression of frzb in whole embryos causes dorsalization, with embryos showing enlarged heads and shortened body axes.

Frzb also inhibits the effect of ectopic Xwnt-8 expression in a non-cell-autonomous manner, suggesting that Frzb functions extracellularly to suppress Wnt function. A related protein, FrzA, when overexpressed in embryos, shows a phenotype similar to that produced by overexpression of frzb in embryos Xu et al. However, frzA is not involved in organizer function because expression commences at the neurula stage in the somitic mesoderm. Organizer Genes Expressed in the Anterior Endomesoderm The identification of genes that are specifically expressed during gastrulation in the anterior endomesoderm has suggested a crucial role of this region as part of the head organizer for the generation of all the anterior structures of an axis.

Etkin The anterior endomesoderm includes the deep dorsoanterior endodermal cells that do not undergo cell involution. The prechordal mesoderm, on the contrary, does involute when the dorsal lip forms. Several genes have been identified in the anterior endomesoderm of the Xenopus head organizer. Xnr-1, -2, and -4, Xblimp, and XHex can regulate specific gene expression in the anterior endomesoderm. The cer and dkk-1 genes encode growth factor antagonist expressed in the anterior endomesoderm and have been suggested to be involved in anterior development.

Genes That Regulate Anterior Endomesoderm Formation Xnr-1 and Xnr-2 are expressed in the anterior endomesoderm as well as the prechordal mesoderm Jones et al. The involvement of the Xnrs in axis induction has been suggested by the observation that a complete secondary axis forms when Xnr-1 is coexpressed with noggin Lustig et al. The use of a cleavage mutant form of Xnr-2, cmXnr2, permits loss-of-function analysis of Xnr Overexpression of cmXnr2 results in anterior truncation and delayed or suppressed expression of dorsoanterior endodermal genes Osada and Wright, A similar phenotype has also been observed with the overexpression of a mutant Activin type II receptor containing the extracellular domain Dyson and Gurdon, or a Smad2 dominant negative construct Hoodless et al.

Oep is membrane-bound and is produced extracellularly in cells responsive to Nodal. Oep functions as an essential cofactor to facilitate Nodal signaling. The mutant phenotype of MZoep can be rescued by overexpressing activin, activated activin receptor, and Smad2. This suggests that Nodal signaling activates an activin-like pathway during early embryonic patterning. In the frog, a temporal and spatial regulation of Nodal signaling is required for the development of the most anterior structures. Maternal factors Vg1, VegT, or both may activate the expression of Xnrs, which induce the formation of the anterior endomesoderm through an activin-like pathway.

It is thought that one of the functions of the anterior endomesoderm is then to create a Nodal-free zone, by the expression of growth factor antagonists, in the anterior endomesoderm within the head organizer for anterior development Piccolo et al. Overexpression of a dominant negative Siamois mutant also represses cer 1. Early Xenopus Development 31 expression in embryos Darras et al.

This indicates that a functional Wnt pathway is required for anterior endomesoderm formation. It is also shown that overexpression of bmp inhibits XHex and cer expression in embryos Zorn et al. Although overexpression of chordin or noggin cannot induce XHex or cer expression, they are required to suppress BMP signaling to maintain XHex and cer expression in the anterior endomesoderm.

Expression of Xblimp1 is detected in the anterior endomesoderm and prechordal mesoderm. Overexpression of Xblimp1 mRNA on the ventral side of the embryo induces dorsoanterior marker genes, including cer, gsc, and Xotx2, but not frzb or dkk This shows that Xblimp is able to regulate expression of specific genes in the anterior endomesoderm. A complete secondary axis can be generated by the overexpression of Xblimp1 and the BMP-antagonist chordin in embryos. XHex is a transcription factor expressed in the anterior endomesoderm Newman et al. The expression domain of XHex largely overlaps with that of cer in the deep dorsal marginal cells in blastula- and gastrula-stage embryos Zorn et al.


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Overexpression of XHex induces cer expression in explants derived from ventral endoderm. The mouse homolog Hex is expressed in the primitive endoderm of mouse blastocysts and later in the visceral endoderm at the distal tip of the egg cylinder Thomas et al. Hex is one of the earliest markers of the anterior visceral endoderm AVE in mouse embryos and is initially detected in the primitive endoderm of blastocysts. The AVE is involved in setting up an early asymmetry of the mouse embryo before the node is formed and has been suggested to be analogous to the anterior endomesoderm in Xenopus Bouwmeester and Leyns, ; Beddington and Robertson, In both mouse and frog embryos, expression of Hex is also detected in the angioblasts, which are precursors for the blood cells and endothelium during vasculogenesis Newman et al.

It has been suggested that Hex could be a marker gene for stem cell populations of endodermal origin. Growth Factor Antagonists Expressed in the Anterior Endomesoderm Cer is a growth factor antagonist expressed in the anterior endomesoderm of Xenopus embryos Bouwmeester et al. Cer contains a single cysteine-rich domain containing conserved cysteine residues and is secreted. In Xenopus, although the anterior endomesoderm does not show any head-inducing property, overexpression of cer can generate ectopic head structures in the absence of a trunk.