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• W2023960686 abstract "In a famous experiment over a century ago, Hans Spemann demonstrated that amphibians have a remarkable ability to compensate for perturbations to the embryo. In this issue of Cell, Reversade and De Robertis, 2005Reversade B. De Robertis E.M. Cell. 2005; (this issue)PubMed Google Scholar uncover the basis of this phenomenon. They demonstrate that interactions between bone morphogenetic proteins (Bmps) and their inhibitors on both the dorsal and ventral sides of the early Xenopus embryo are involved in creating the body plan. In a famous experiment over a century ago, Hans Spemann demonstrated that amphibians have a remarkable ability to compensate for perturbations to the embryo. In this issue of Cell, Reversade and De Robertis, 2005Reversade B. De Robertis E.M. Cell. 2005; (this issue)PubMed Google Scholar uncover the basis of this phenomenon. They demonstrate that interactions between bone morphogenetic proteins (Bmps) and their inhibitors on both the dorsal and ventral sides of the early Xenopus embryo are involved in creating the body plan. In one of the great pioneering experiments in the field of developmental biology, Hans Spemann divided amphibian embryos at the two-cell stage into separate halves by ligation with a human baby's hair and then monitored the ability of the two halves to generate a complete amphibian body plan (discussed in English in Spemann, 1938Spemann H. Embryonic Development and Induction. Yale University Press, New Haven, CT1938Crossref Google Scholar). If the embryos were separated along the typical plane of cleavage, which separates the left and right sides of the embryo, two fully formed twins developed. Remarkably, however, if two-cell frog embryos were split perpendicular to the typical cleavage plane resulting in dorsal and ventral halves of the embryo, a very different result was observed. One of the cells developed into a relatively disorganized mass of tissue that Spemann called the bauchstück (belly piece) as it contained no dorsal structures (see Figure 1A ). Surprisingly, the other cell developed into a relatively well-proportioned embryo. Spemann's results showed that the amphibian embryo has the ability to compensate for the missing ventral half (called self-regulation). How this self-regulation works at a molecular level has been a mystery that has lasted for more than a hundred years. Since Spemann's original ligation experiment, a great deal has been learned about the mechanisms that pattern the early amphibian embryo. Soon after fertilization, a “dorsalizing activity” moves from the bottom of the embryo toward one side, which will become the future dorsal-anterior pole. By default, the opposite side will become the ventral-posterior pole (for simplicity, these will be referred to as the dorsal and ventral poles of the embryo). The dorsalizing activity locally stabilizes β-catenin, the Wnt intracellular signal transducer, which subsequently activates genes involved in forming an important signaling center called the Spemann organizer. The Spemann organizer acts during the gastrula stage to pattern the embryo, and it is now known that this organizer secretes a number of important factors, particularly inhibitors of the Bmp pathway (reviewed in De Robertis and Kuroda, 2004De Robertis E.M. Kuroda H. Annu. Rev. Cell Dev. Biol. 2004; 20: 285-308Crossref PubMed Scopus (518) Google Scholar). The Bmp inhibitors include Chordin, Noggin, and Follistatin, which act in an overlapping manner to promote dorsal fates (Khokha et al., 2005Khokha M.K. Yeh J. Grammer T.C. Harland R.M. Dev. Cell. 2005; 8: 401-411Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar). On the opposite side of the embryo, Bmp4 is expressed and it works together with Bmp2 and Bmp7 to promote ventral fates (Reversade et al., 2005Reversade B. Kuroda H. Lee H. Mays A. De Robertis E.M. Development. 2005; 132: 3381-3392Crossref PubMed Scopus (105) Google Scholar). Patterning of tissues in the gastrula-stage embryo essentially involves a contest between the dorsal and ventral sides, each antagonizing the other (see Figure 1B). Bmp signaling upregulates a set of transcriptional repressors, known as Xvents in Xenopus, which inhibit the expression of the organizer genes encoding the Bmp inhibitors. In contrast, dorsally secreted Bmp inhibitors prevent the Bmps from promoting ventral fates by blocking the interaction of Bmps with their receptors (see Figure 1B). These interactions create different levels of Bmp signaling on the dorsal and ventral sides of the embryo. This distinction is necessary for subdividing the germ layers into different fates. In the upper portion of the embryo, the ectoderm is subdivided into neural tissue on the dorsal side and epidermis on the ventral side. At the equator, the mesoderm is subdivided into dorsal tissues such as head mesoderm and notochord, whereas the ventral side gives rise to tissues such as tail muscle and kidney cells. Although this model has received a large amount of experimental support, it fails to explain Spemann's experiment. If the ventral side is cut away, as in Spemann's original ligation experiment, the dorsal fragment would be expected to only produce dorsal fates, as the cells expressing Bmp2/4/7 have been excised. In their new study, Reversade and De Robertis, 2005Reversade B. De Robertis E.M. Cell. 2005; (this issue)PubMed Google Scholar predict that another Bmp must be compensating for the missing Bmps. The Bmp they choose to investigate as a candidate is Admp. The function of Admp has always been a puzzle because it is expressed on the dorsal side of the embryo, where Bmp inhibitors are acting to antagonize ventral fates (Moos et al., 1995Moos Jr., M. Wang S. Krinks M. Development. 1995; 121: 4293-4301PubMed Google Scholar). Nonetheless, in zebrafish, which also express Admp on the dorsal side of the embryo, knockdown of the Admp protein results in embryos with an enhanced dorsal phenotype (dorsalized embryos). This demonstrates that Admp, like the other Bmps, promotes ventral fates (Lele et al., 2001Lele Z. Nowak M. Hammerschmidt M. Dev. Dyn. 2001; 222: 681-687Crossref PubMed Scopus (41) Google Scholar, Willot et al., 2002Willot V. Mathieu J. Lu Y. Schmid B. Sidi S. Yan Y.L. Postlethwait J.H. Mullins M. Rosa F. Peyrieras N. Dev. Biol. 2002; 241: 59-78Crossref PubMed Scopus (36) Google Scholar). Similarly, in Xenopus, Reversade and De Robertis, 2005Reversade B. De Robertis E.M. Cell. 2005; (this issue)PubMed Google Scholar find that knockdown of Admp produces dorsalized embryos. Of greater interest, however, is that when they repeat Spemann's experiment on embryos expressing reduced Admp protein, they find that self-regulation is largely absent in the dorsal halves, as evidenced by the widespread expression of a neural marker. As the authors only characterize this one marker, it is not certain what happens to mesodermal fates, but the presumption is that they also would be dorsalized. This experiment provides the critical evidence that Admp plays an essential role in the self-regulation process. In order for the dorsal halves to self-regulate and develop into normal embryos, a zone of Bmp-type signaling needs to be created away from the organizer to promote ventral fates (see Figure 1C). For Admp to establish this zone of signaling, it needs to generate a region of high Bmp activity away from the dorsal source of Chordin, which can bind and inactivate it. There are at least two possibilities for how this might occur. Chordin and Admp could both be expressed on the dorsal side of the dorsal half-embryos, but the Admp might diffuse further than the Chordin, creating a zone that is Admp rich and Chordin poor. In zebrafish, epitope-tagged Admp diffuses over considerable distances (Willot et al., 2002Willot V. Mathieu J. Lu Y. Schmid B. Sidi S. Yan Y.L. Postlethwait J.H. Mullins M. Rosa F. Peyrieras N. Dev. Biol. 2002; 241: 59-78Crossref PubMed Scopus (36) Google Scholar). Reversade and De Robertis, 2005Reversade B. De Robertis E.M. Cell. 2005; (this issue)PubMed Google Scholar also provide indirect evidence for long-range diffusion of Admp in Xenopus. An alternative is transcriptional upregulation of Admp on the ventral side of the half-embryos, because Admp is expressed when the levels of Bmp signaling are low or absent. Thus, when the ventral half is cut off (removing the source of Bmps), Admp may begin to be expressed on the ventral side of the dorsal half-embryo, providing a ventral Bmp-type signal (see Figure 1C). Distinguishing between these two possibilities will be important for more fully understanding the mechanism of self-regulation. What is Admp actually doing on the dorsal side of the embryo during normal development? Studies in zebrafish show that it acts to limit the size of the organizer by inhibiting the expression of organizer genes (Lele et al., 2001Lele Z. Nowak M. Hammerschmidt M. Dev. Dyn. 2001; 222: 681-687Crossref PubMed Scopus (41) Google Scholar, Willot et al., 2002Willot V. Mathieu J. Lu Y. Schmid B. Sidi S. Yan Y.L. Postlethwait J.H. Mullins M. Rosa F. Peyrieras N. Dev. Biol. 2002; 241: 59-78Crossref PubMed Scopus (36) Google Scholar). Reversade and De Robertis, 2005Reversade B. De Robertis E.M. Cell. 2005; (this issue)PubMed Google Scholar arrive at the same conclusion in Xenopus. Yet it is the relationship between Chordin and Admp that is particularly intriguing: Chordin binds to Admp and prevents it from interacting with its receptor. Using Bmp4 as a likely analog for Admp, the authors argue that Admp inhibits Chordin expression. They postulate that Admp and Chordin exist in a mutual repressor loop on the dorsal side of the embryo (see Figure 1D). However, the situation is more complex than this, given that, as discussed above, Admp is only expressed when the level of Bmp (and Admp) signaling is low or absent, which is likely to require Chordin function (along with the functions of other dorsally expressed Bmp inhibitors). Thus, Chordin not only inhibits Admp function, but it appears to be necessary for Admp expression, indicating that Chordin and Admp exist in a complex dynamic equilibrium, where each factor regulates the other (see Figure 1D). Similarly, on the ventral side of the embryo, Bmps 2, 4, and 7 and the Bmp inhibitors Sizzled and Bambi may exist in another self-regulating signaling center (see Figure 1D). Bmp4 positively regulates its own transcription, but it also activates Bambi and Sizzled expression, which inhibit this autoregulatory loop and decrease the expression of all three factors. The interactions between the Bmps and their inhibitors presumably act to establish the correct level of Bmp activity. Thus, in the new model, two sources of Bmps and Bmp inhibitors are generated at the ventral and dorsal poles of the embryo to establish normal patterning; in the traditional view, only ventral Bmps and dorsal Bmp inhibitors create the Bmp gradient (compare Figure 1B to Figure 1D). This raises an important question: why is there so much complexity in the regulation of Bmp signaling? Given that different levels of Bmp activity in the gastrula-stage embryo act to specify distinct tissue types, clearly it is crucial to have tight regulation of Bmp signaling across the dorsal-ventral axis. Bmp signaling continues to be important as cells move during gastrulation (Pyati et al., 2005Pyati U.J. Webb A.E. Kimelman D. Development. 2005; 132: 2333-2343Crossref PubMed Scopus (115) Google Scholar). The dynamic regulation of Bmp signaling described by Reversade and De Robertis, 2005Reversade B. De Robertis E.M. Cell. 2005; (this issue)PubMed Google Scholar would allow tight regulation of Bmp signaling even as the embryo is undergoing widespread morphological changes. With a deeper understanding of the basic mechanism of self-regulation in the amphibian embryo, the challenge now will be to elucidate how this process operates in time and space as cells proceed through the complex morphogenetic movements of gastrulation." @default.
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• W2023960686 title "Bmp Signaling: Turning a Half into a Whole" @default.
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