Spemann Research Articles

‘Big frog, small frog’– maintaining proportions in embryonic development

We discuss mechanisms that enable the scaling of pattern with size during the development of multicellular organisms. Recently, we analyzed scaling in the context of the early Xenopus embryo, focusing on the determination of the dorsal-ventral axis by a gradient of BMP activation. The ability of this system to withstand extreme perturbation was exemplified in classical experiments performed by Hans Spemann in the early 20th century. Quantitative analysis revealed that patterning is governed by a noncanonical 'shuttling-based' mechanism, and defined the feedback enabling the scaling of pattern with size. Robust scaling is due to molecular implementation of an integral-feedback controller, which adjusts the width of the BMP morphogen gradient with the size of the system. We present an 'expansion-repression' feedback topology which generalizes this concept for a wider range of patterning systems, providing a general, and potentially widely applicable model for the robust scaling of morphogen gradients with size.

Scaling of the BMP activation gradient in Xenopus embryos

In groundbreaking experiments, Hans Spemann demonstrated that the dorsal part of the amphibian embryo can generate a well-proportioned tadpole, and that a small group of dorsal cells, the 'organizer', can induce a complete and well-proportioned twinned axis when transplanted into a host embryo. Key to organizer function is the localized secretion of inhibitors of bone morphogenetic protein (BMP), which defines a graded BMP activation profile. Although the central proteins involved in shaping this gradient are well characterized, their integrated function, and in particular how pattern scales with size, is not understood. Here we present evidence that in Xenopus, the BMP activity gradient is defined by a 'shuttling-based' mechanism, whereby the BMP ligands are translocated ventrally through their association with the BMP inhibitor Chordin. This shuttling, with feedback repression of the BMP ligand Admp, offers a quantitative explanation to Spemann's observations, and accounts naturally for the scaling of embryo pattern with its size.

EGF receptor signaling — a quantitative view

Almost a century ago, the experiments of Hans Spemann and Hilde Mangold on transplantation of cells between Xenopus embryos demonstrated that the body plan is determined by intricate communication between cells. Today, through genetic, molecular and biochemical analyses, we know the major signaling pathways that mediate these interactions and many of their molecular constituents, which are highly conserved in evolution. Despite mechanistic differences between the pathways, the general mode through which they function is similar.

From Genes to Embryo and Beyond

The study of embryology goes back to the nineteenth century when Karl Ernst von Baer recognized that there are similarities between embryos of different species and that those similarities disappear as the embryos mature into adults. This notion was later observed and studied by Charles Darwin, who established the idea of a common ancestor to explain embryological similarities. Developmental biology has been growing exponentially as a field since the 1970s when biochemical techniques and later on molecular techniques allowed most of the studies that have defined the field to its current status. Nobel Laureate Christiane Nusslein-Volhard, who pioneered along with Eric Wieschaus the discovery of genes that guide development in the fruit fly Drosophila, has taken on the gigantic task of writing a historical and sociopolitical account of developmental biology primarily for a lay audience. No one is more qualified than Nusslein-Volhard because she has carried out pioneering developmental genetics work in invertebrates and more recently in the vertebrate zebrafish (Danio rerio) and currently directs the Max Planck Institute for Developmental Biology in Tubingen, Germany. Coming to Life, with a main text of 145 pages, addresses in 10 chapters major highlights that have shaped the field of developmental biology and how current scientific and social issues can be understood and perhaps adequately addressed in light of a more accurate understanding of embryonic development. The first nine chapters take the reader to various milestones in genetics, development, and biology in general. Each one of these nine chapters includes hand-drawn figures, which give a personal touch to the narrative and perhaps makes the content less intimidating to the layperson. The last chapter, “Current Topics,” is the author's personal manifesto of how to use understanding of development to be well-educated consumers of science and some of the issues that emerge from misuses and misunderstandings of scientific information.

An essential role for FGF receptor signaling in lens development

Since the days of Hans Spemann, the ocular lens has served as one of the most important developmental systems for elucidating fundamental processes of induction and differentiation. More recently, studies in the lens have contributed significantly to our understanding of cell cycle regulation and apoptosis. Over 20 years of accumulated evidence using several different vertebrate species has suggested that fibroblast growth factors (FGFs) and/or fibroblast growth factor receptors (FGFRs) play a key role in lens development. FGFR signaling has been implicated in lens induction, lens cell proliferation and survival, lens fiber differentiation and lens regeneration. Here we will review and discuss historical and recent evidence suggesting that (FGFR) signaling plays a vital and universal role in multiple aspects of lens development.

Mosaic and regulative development: two faces of one coin

“There seems to be no more a completely mosaic egg than a completely regulation one” Waddington, Principles of Embryology 1956, Allen and Unwin, p63.

Bmp Signaling: Turning a Half into a Whole

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 (2005) 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.

Mechanism, vitalism and organicism in late nineteenth and twentieth-century biology: the importance of historical context

The term ‘mechanism’ has been used in two quite different ways in the history of biology. Operative, or explanatory mechanism refers to the step-by-step description or explanation of how components in a system interact to yield a particular outcome (as in the ‘mechanism of enzyme action’ or the ‘mechanism of synaptic transmission’). Philosophical Mechanism, on the other hand, refers to a broad view of organisms as material entities, functioning in ways similar to machines — that is, carrying out a variety of activities based on known chemical and physical processes. In the early twentieth century philosophical Mechanism became the foundation of a ‘new biology’ that sought to establish the life sciences on the same solid and rigorous foundation as the physical sciences, including a strong emphasis on experimentation. In the context of the times this campaign was particularly aimed at combating the reintroduction of more holistic, non-mechanical approaches into the life sciences (organicism, vitalism). In so doing, Mechanists failed to see some of the strong points of non-vitalistic holistic thinking. The two approaches are illustrated in the work of Jacques Loeb and Hans Spemann.

Newts

Newts

317-THE DEVELOPMENT AND SIGNIFICANCE OF TYPE C

A hallmark of embryonic development is the temporal-spatial continuum of cell–cell interactions, which gives rise to the trajectory of progressive cell differentiations. Despite the great reductionists' success in dissecting the mechanistic basis of developmental processes, the call for more holistic system theories never ceased during the last century. Various system theories were proposed to provide a more adequate understanding of biological systems, including development. Although widely ignored by modern biology, the first systematic system theory was Hegel's dialectics. Here I examine the process of embryonic induction as elaborated by Hans Spemann in the light of dialectics. I conclude that embryonic induction and its underlying molecular mechanisms can be re-interpreted in terms of Hegel's dialectics. The example highlights that despite its shortcomings, dialectics can be of heuristic value as a theory of systems biology.

Organizing the vertebrate embryo--a balance of induction and competence.

In what is usually referred to as the most famous experiment in embryology, Hans Spemann and Hilde Mangold (1924) showed that a specific region in early frog embryos called the blastopore lip can induce a second complete embryonic axis, including the head, when transplanted to a host embryo. Most of the axis, including the nervous system, was derived from the host, whose cells were induced to form an axis by the graft, therefore named the organizer. Induction refers to the change in fate of a group of cells in response to signals from other cells. The signal-receiving cells must be capable of responding, a property termed competence. The Spemann–Mangold organizer. which—as the transplantation experiment shows—is able to turn cells whose original fate would be gut or ventral epidermis into brain or somites, is the prototypical inducing tissue. And neural induction has for a long time been regarded as a process by which organizer signals, in their normal context, redirect ectodermal cells from an epidermal towards a neural fate. The nature of the neural inducer or inducers and the mechanism of neural induction have been and remain hot topics in developmental biology.

Yves Delage (1854-1920) as a forerunner of modern nuclear transfer experiments.

It is generally considered that animal cloning by nuclear transfer originated in proposals made by Hans Spemann (1936), following his experiments on delayed nucleation in the newt egg, which were preceded by similar attempts using the sea-urchin egg (Loeb, 1894). Briggs and King (1952) were the first to succeed in transplanting blastula and gastrula nuclei into the enucleated frog egg and in obtaining a significant number of normal tadpoles by means of this technique. We present evidence that much earlier (1895) Yves Delage (1854-1920), a French biologist, had clearly formulated the same experimental project of nuclear transfer, as a means to test Weismann's theory of cell differentiation during embryonic development. This was also Spemann's motivation. Both Delage and Spemann were aware of Loeb's experiments (1894), in which delayed nucleation in the sea-urchin egg was found to result in twin larvae. It is difficult to decide whether Delage's project was influenced by Loeb's findings. On the other hand, it seems that Spemann was not aware of Delage's proposal, since he did not express his own ideas on extended nuclear transfer before 1936. Finally, neither Delage nor Spemann imagined that nuclear transfer could be a means of obtaining groups of genetically identical animals (reproductive cloning).

A Pact with the Embryo: Viktor Hamburger, Holistic and Mechanistic Philosophy in the Development of Neuroembryology, 1927?1955

Viktor Hamburger was a developmental biologist interested in the ontogenesis of hte vertebrate nervous system. A student of Hans Spemann at Freiburg in the 1920s, Hamburger picked up a holistic view of the embryo that precluded him from treating it in a reductionist way; at the same time, he was committed to a materialist and analytical approach that eschewed any form of vitalism or metaphysics. This paper explores how Hamburger walked this thin line between mechanistic reductionism and metaphysical vitalism in light of his work on the factors influencing growth of neurons into limb buds, and the discovery of nerve growth factor, work carried out with Rita Levi-Montalcini and Stanley Cohen.

Ontogeny, Anatomy, and the Problem of Homology: Carl Gegenbaur and the American Tradition of Cell Lineage Studies

Summary In this paper we analyze Carl Gegenbaur's conception of the relationship between embryology (“Ontogenie”) and comparative anatomy and his related ideas about homology. We argue that Gegenbaur's conviction of the primacy of comparative anatomy and his careful consideration of caenogenesis led him to a more balanced view about the relationship between ontogeny and phylogeny than his good friend Ernst Haeckel. We also argue that Gegenbaur's ideas about the centrality of comparative anatomy and his definitions of homology actually laid the conceptual foundations for Hans Spemann's (1915) later analysis of homology. We also analyze Gegenbaur's reception in the United States and how the discussions between E.B. Wilson and Edwin Conklin about the role of the “embryological criterion of homology” and the latter's argument for an even earlier concept of cellular homology reflect the recurring theme of preformism in ontogeny, a theme that finds its modern equivalent in various genetic definitions of homology, only recently challenged by the emerging synthesis of evolutionary developmental biology. Finally, we conclude that Gegenbaur's own careful methodological principles can serve as an important model for proponents of present day “evo-devo”, especially with respect to the integration of ontogeny withphylogeny embedded in comparative anatomy.

New twists on embryonic patterning. EMBO workshop: embryonic organizer signaling: the next frontiers.

The EMBO workshop ‘Embryonic organizer signaling: the next frontiers’ was held at the European Molecular Biology Laboratory in Heidelberg, Germany, April 28–30, 2001. ![][1] The term ‘organizer’ was coined by Hans Spemann and Hilde Mangold in 1924, based on the seminal observation that a small region of the amphibian gastrula, the dorsal lip, when transplanted to an ectopic location, had the ability to induce, or organize, the formation of a twinned embryo, recruiting neighboring cells from the host into a variety of cell differentiation pathways. The gastrula organizer has been reviewed in extenso recently (special issue of Int. J. Dev. Biol. , 45 ). It has become apparent that organizing centers, which secrete signals that pattern adjacent regions, are a recurring theme in developmental biology. Organizing centers function during neural tube formation in vertebrates, compartment boundary formation in Drosophila , limb development and the establishment of left–right asymmetry. Intercellular signaling is effected through a surprisingly small number of cell surface receptor‐mediated signaling pathways, in particular Hedgehog, Wnt, FGF, Delta/Notch and TGF‐β family members. Molecular and genetic studies on the various organizing centers have revealed that these signaling pathways are highly modulated, by agonist and antagonist signals and a variety of post‐translational modifications, to generate the intricate patterns observed in developing embryos. The complexity, mechanisms of action and the conceptual convergence/divergence of distinct embryonic organizer centers was discussed at the EMBO workshop on ‘Embryonic organizer signaling: the next frontiers’ held at the EMBL on April 28–30, 2001 in Heidelberg. In this review, we highlight some of the salient themes that emerged. ### Secreted antagonists, inhibitory modulation of growth factor activity A major conclusion to emerge in recent years is that embryonic patterning is controlled to a large extent by the modulatory action of secreted antagonists or agonists (Figure 1). For example, Chordin and Noggin are antagonists secreted by the gastrula organizer, which … [1]: /embed/graphic-1.gif

Developmental biology of amphibians after Hans Spemann in Germany.

After the Hans Spemann and Hilde Mangold discovery of the importance of the dorsal blastopore lip for axis formation in the early embryo (Nobelprize for Spemann, 1935), the scientific community tried in a goldrush-like manner to find the inducing factors responsible for the programming of early embyronic determination and differentiation. The slow progress towards a solution of this problem caused a fading of interest on behalf of most laboratories. This article describes the activities of a few laboratories in Finland, Japan and Germany, which continued their studies despite tremendous experimental difficulties. Finally only Heinz Tiedemann's group in Berlin was the first which could isolate a mesoderm/endoderm inducing factor in highly purified form, the so-called vegetalizing factor, now known as activin. Furthermore this article describes the identification of neuralizing factors like Chordin, Cerberus and Dickkopf in the zone of the Spemann-Mangold organizer. The finding that BMP-4 acts as an antagonist to these factors located on the dorsal side led to a new understanding of the mechanisms of action of inducing (neuralizing) factors and early embryonic pattern formation. Moreover, the observations that closely related genes and their products were also found in Drosophila, Zebrafish, Mice and Human were the basis for new concepts of evolutionary mechanisms (dorsal/ventral and anterior/posterior polarity or conserved processes in eye-development of all 7 animal phyla).

The Spemann-Mangold organizer: the control of fate specification and morphogenetic rearrangements during gastrulation in Xenopus.

Vertebrate embryonic development is controlled by sequentially operating signalling centres that organize spatial pattern by inductive interactions. The embryonic body plan is established during gastrulation through the action of the Spemann-Mangold or gastrula organizer, a signalling source discovered 75 years ago by Hans Spemann and Hilde Mangold. Transplantation of the organizer to a heterotopic location in a recipient embryo results in the formation of a secondary embryonic body axis, in which several tissue types, most notably somites and the neural tube, are derived from ventral host cells. Because of these non-cell autonomous recruiting or inducing activities the organizer has become a paradigm for studying intercellular communication in the vertebrate embryo. Here, I review some of the recent advances in understanding 1) the initiation of the Spemann-Mangold organizer, 2) its function in pattern formation along the dorsal-ventral and anterior-posterior axes and 3) the integration of cell fate specification events and downstream execution of morphogenetic movements during gastrulation in Xenopus laevis.

Introducing the Spemann-Mangold organizer: experiments and insights that generated a key concept in developmental biology.

The "organizer paper", published by Hans Spemann and Hilde Mangold in 1924, initiated a new epoch in developmental biology. Also it marked the climax of Spemann's life-long research which began at the end of the nineteenth century. This introduction retraces some of the steps by which Spemann arrived at the organizer concept: The problem of amphibian lens induction including the so-called lens controversy, the early constriction experiments creating double headed malformations, and the homeo- and heteroplastic transplantations during gastrula stages of the newt. Furthermore this paper will--based on historical documents--repudiate some objections raised to the contribution of Spemann and Hilde Mangold to the discovery and interpretation of the organizer effect.

Homology in Development and the Development of the Homology Concept

Homology is a central concept for Developmental Evolution. Here I argue that homology should be explained within the reference processes of development and evolution; development because it is the proximate cause of morphological characters and evolution because it deals with organic transformations and stability. This was already recognized by Hans Spemann in 1915. In a seminal essay “A history and critique of the homology concept” Spemann analyzed the history and present problems of the homology concept. Here I will continue Spemann's project and analyze some of the 20th century contributions to homology. I will end with a few reflections about the connections between developmental processes and homology and conclude that developmental processes are inherent in (i) the assessment of homology, (ii) the explanation of homology, (iii) the origin of evolutionary innovations (incipient homologues), and (iv) can be considered homologous themselves.

Homology in Development and the Development of the Homology Concept1

Homology is a central concept for Developmental Evolution. Here I argue that homology should be explained within the reference processes of development and evolution; development because it is the proximate cause of morphological characters and evolution because it deals with organic transformations and stability. This was already recognized by Hans Spemann in 1915. In a seminal essay “A history and critique of the homology concept” Spemann analyzed the history and present problems of the homology concept. Here I will continue Spemann's project and analyze some of the 20th century contributions to homology. I will end with a few reflections about the connections between developmental processes and homology and conclude that developmental processes are inherent in (i) the assessment of homology, (ii) the explanation of homology, (iii) the origin of evolutionary innovations (incipient homologues), and (iv) can be considered homologous themselves.