In avian and mammalian embryos the \"organizer\" property associated with neural induction of competent ectoderm into a neural plate and its subsequent patterning into rostro-caudal domains resides at the tip of the primitive streak before neurulation begins, and before a morphological Hensen\'s node is discernible. The same region and its later derivatives (like the notochord) also have the ability to \"dorsalize\" the adjacent mesoderm, for example by converting lateral plate mesoderm into paraxial (pre-somitic) mesoderm. Both neural induction and dorsalization of the mesoderm involve inhibition of BMP, and the former also requires other signals. This review surveys the key experiments done to elucidate the functions of the organizer and the mechanisms of neural induction in amniotes. We conclude that the mechanisms of neural induction in amniotes and anamniotes are likely to be largely the same; apparent differences are likely to be due to differences in experimental approaches dictated by embryo topology and other practical constraints. We also discuss the relationships between \"neural induction\" assessed by grafts of the organizer and normal neural plate development, as well as how neural induction relates to the generation of neuronal cells from embryonic and other stem cells in vitro.

This article is about how the famous organizer experiment has been perceived since it was first published in 1924. The experiment involves the production of a secondary embryo under the influence of a graft of a dorsal lip from an amphibian gastrula to a host embryo. The early experiments of Spemann and his school gave rise to a view that the whole early amphibian embryo was \"indifferent\" in terms of determination, except for a special region called \"the organizer\". This was viewed mainly as an agent of neural induction, also having the ability to generate an anteroposterior body pattern. Early biochemical efforts to isolate a factor emitted by the organizer were not successful but culminated in the definition of \"neuralizing (N)\" and \"mesodermalizing (M)\" factors present in a wide variety of animal tissues. By the 1950s this view became crystallized as a \"two gradient\" model involving the N and M factors, which explained the anteroposterior patterning effect. In the 1970s, the phenomenon of mesoderm induction was characterized as a process occurring before the commencement of gastrulation. Reinvestigation of the organizer effect using lineage labels gave rise to a more precise definition of the sequence of events. Since the 1980s, modern research using the tools of molecular biology, combined with microsurgery, has explained most of the processes involved. The organizer graft should now be seen as an experiment which involves multiple interactions: dorsoventral polarization following fertilization, mesoderm induction, the dorsalizing signal responsible for neuralization and dorsoventral patterning of the mesoderm, and additional factors responsible for anteroposterior patterning.

Embryonic induction is a key mechanism in development that corresponds to an interaction between a signalling and a responding tissue, causing a change in the direction of differentiation by the responding tissue. Considerable progress has been achieved in identifying inductive signals, yet how tissues control their responsiveness to these signals, known as competence, remains poorly understood. While the role of molecular signals in competence has been studied, how tissue mechanics influence competence remains unexplored. Here we investigate the role of hydrostatic pressure in controlling competence in neural crest cells, an embryonic cell population. We show that neural crest competence decreases concomitantly with an increase in the hydrostatic pressure of the blastocoel, an embryonic cavity in contact with the prospective neural crest. By manipulating hydrostatic pressure in vivo, we show that this increase leads to the inhibition of Yap signalling and impairs Wnt activation in the responding tissue, which would be required for neural crest induction. We further show that hydrostatic pressure controls neural crest induction in amphibian and mouse embryos and in human cells, suggesting a conserved mechanism across vertebrates. Our work sets out how tissue mechanics can interplay with signalling pathways to regulate embryonic competence.

Lamprey homologues of the classic embryonic inducer Noggin are similar in expression pattern and functional properties to Noggin homologues of jawed vertebrates. All noggin genes of vertebrates apparently originated from a single ancestral gene as a result of genome duplications. nogginA, nogginB and nogginC of lampreys, like noggin1 and noggin2 of gnathostomes, demonstrate the ability to induce complete secondary axes with forebrain and eye structures when overexpressed in Xenopus laevis embryos. According to current views, this finding indicates the ability of lamprey Noggin proteins to suppress the activity of the BMP, Nodal/Activin and Wnt/beta-catenin signaling pathways, as shown for Noggin proteins of gnathostomes. In this work, by analogy with experiments in Xenopus embryos, we attempted to induce secondary axes in the European river lamprey Lampetra fluviatilis by injecting noggin mRNAs into lamprey eggs in vivo. Surprisingly, unlike what occurs in amphibians, secondary axis induction in the lampreys either by noggin mRNAs or by chordin and cerberus mRNAs, the inductive properties of which have been described, was not observed. Only wnt8a mRNA demonstrated the ability to induce secondary axes in the lampreys. Such results may indicate that the mechanism of axial specification in lampreys, which represent jawless vertebrates, may differ in detail from that in the jawed clade.

The discovery of the Spemann-Mangold organizer strongly influenced subsequent research on embryonic induction, with research aiming to elucidate the molecular characteristics of organizer activity being currently underway. Herein, we review the history of research on embryonic induction, and describe how the mechanisms of induction phenomena and developmental processes have been investigated. Classical experiments investigating the differentiation capacity and inductive activity of various embryonic regions were conducted by many researchers, and important theories of region-specific induction and the concept for chain of induction were proposed. The transition from experimental embryology to developmental biology has enabled us to understand the mechanisms of embryonic induction at the molecular level. Consequently, many inducing substances and molecules such as transcriptional factors and peptide growth factors involved in the organizer formation were identified. One of peptide growth factors, activin, acts as a mesoderm- and endoderm-inducing substance. Activin induces several tissues and organs from the undifferentiated cell mass of amphibian embryos in a concentration-dependent manner. We review the extent to which we can control in vitro organogenesis from undifferentiated cells, and discuss the application to stem cell-based regenerative medicine based on insights gained from animal experiments, such as in amphibians.

Neural induction by cell-cell signaling was discovered a century ago by the organizer transplantations of Spemann and Mangold in amphibians. Spemann later found that early dorsal blastopore lips induced heads and late organizers trunk-tail structures. Identifying region-specific organizer signals has been a driving force in the progress of animal biology. Head induction in the absence of trunk is designated archencephalic differentiation. Two specific head inducers, Cerberus and Insulin-like growth factors (IGFs), that induce archencephalic brain but not trunk-tail structures have been described previously. However, whether these two signals interact with each other had not been studied to date and was the purpose of the present investigation. It was found that Cerberus, a multivalent growth factor antagonist that inhibits Nodal, BMP and Wnt signals, strongly cooperated with IGF2, a growth factor that provides a positive signal through tyrosine kinase IGF receptors that activate MAPK and other pathways. The ectopic archencephalic structures induced by the combination of Cerberus and IGF2 are of higher frequency and larger than either one alone. They contain brain, a cyclopic eye and multiple olfactory placodes, without trace of trunk structures such as notochord or somites. A dominant-negative secreted IGF receptor 1 blocked Cerberus activity, indicating that endogenous IGF signals are required for ectopic brain formation. In a sensitized embryonic system, in which embryos were depleted of β-catenin, IGF2 did not by itself induce neural tissue while in combination with Cerberus it greatly enhanced formation of circular brain structures expressing the anterior markers Otx2 and Rx2a, but not spinal cord or notochord markers. The main conclusion of this work is that IGF provides a positive signal initially uniformly expressed throughout the embryo that potentiates the effect of an organizer-specific negative signal mediated by Cerberus. The results are discussed in the context of the history of neural induction.

The history of developmental biology starts from the almost simultaneous discoveries of the Organizer of axial structures in amphibians by Spemann and Mangold in Freiburg and of the Brachyury mutant in mammals by the Dobrovolskaya-Zavadskaya laboratory at the Curie Institute and its follow-up studies in the Leslie Dunn laboratory at Columbia University. Following the Organizer\'s discovery, the inductive activity of several other embryonic tissues was found, including that of the ear primordium by Boris Balinsky in Kiev. Initially, the experimental embryological and genetic lines of research existed independently of each other, but after they met at the bench of Salome Gluecksohn, they strengthened and cross-fertilized each other, eventually leading to developmental genetics, which later became known as developmental biology. It appears that the regulatory activities of Brachyury and related T-box proteins in general are at the heart of the development of all vertebrates. These activities are fundamental and have been discovered in several model organisms subjected to mutagenesis, exemplified by the story of George Streisinger\'s discovery of the no tail mutant in zebrafish. This essay describes the history of Brachyury studies, their connection to an idea of embryonic induction by Organizer, and an impact of Brachyury and related genes on various fields of research from embryology and cell biology to medical genetics and evolutionary theory.

The present molecular investigations of Organizer phenomena show a remarkable connection to the earlier classical embryological studies that used transplantation as a method for making mechanistic models of induction. One of the most prominent of these connections is the dual gradient model for anterior-posterior and dorsal-ventral polarity. This paper will discuss some of the history of how transplantation experiments provided data that could be interpreted in terms of two gradients of biologically active materials. It will highlight how the attempts to discover the elusive Induktionsstoffen gave rise to the double gradient model of Sulo Toivonen and Lauri Saxén in the 1950s and 1960s. This paper will also document how this research into the identity of these molecules gave rise to the developmental genetics that eventually would find the molecules responsible for primary embryonic induction.

Development of the central nervous system in amphibians has called attention from scientists for over a century. Interested in the matter of embryonic inductions, Hans Spemann and Hilde Mangold found out that the dorsal blastopore lip of the salamander\'s embryo has organizer properties. Such an ectopic graft could induce structures in the host embryo, including a neural tube overlying the notochord of a perfect secondary body axis. A couple of decades later, the frog Xenopus laevis emerged as an excellent embryological experimental model and seminal concepts involving embryonic inductions began to be revealed. The so-called primary induction is, in fact, a composition of signaling and inductive events that are triggered as soon as fertilization takes place. In this regard, since early 1990s an intricate network of signaling pathways has been built. The Wnt pathway, which began to be uncovered in cancer biology studies, is crucial during the establishment of two signaling centers in Xenopus embryogenesis: Nieuwkoop center and the blastula chordin noggin expression center (BCNE). Here we will discuss the historical events that led to the discovery of those centers, as well as the molecular mechanisms by which they operate. This chapter highlights the cooperation of both signaling centers with potential to be further explored in the future. We aim to address the essential morphological transformation during gastrulation and neurulation as well as the role of Wnt signaling in patterning the organizer and the neural plate.

During early vertebrate development, signals from a special region of the embryo, the organizer, can redirect the fate of non-neural ectoderm cells to form a complete, patterned nervous system. This is called neural induction and has generally been imagined as a single signalling event, causing a switch of fate. Here, we undertake a comprehensive analysis, in very fine time course, of the events following exposure of competent ectoderm of the chick to the organizer (the tip of the primitive streak, Hensen\'s node). Using transcriptomics and epigenomics we generate a gene regulatory network comprising 175 transcriptional regulators and 5614 predicted interactions between them, with fine temporal dynamics from initial exposure to the signals to expression of mature neural plate markers. Using in situ hybridization, single-cell RNA-sequencing, and reporter assays, we show that the gene regulatory hierarchy of responses to a grafted organizer closely resembles the events of normal neural plate development. The study is accompanied by an extensive resource, including information about conservation of the predicted enhancers in other vertebrates.