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PubMed1996

Determination of neuroepithelial cell fate: induction of the oligodendrocyte lineage by ventral midline cells and sonic hedgehog.

Near the floor plate of the embryonic neural tube there is a group of neuroepithelial precursor cells that are specialized for production of the oligodendrocyte lineage. We performed experiments to test whether specification of these neuroepithelial oligodendrocyte precursors, like other ventral neural cell types, depends on signals from the notochord and/or floor plate. We analyzed heterozygous Danforth's short tail (Sd/+) mutant mice, which lack a notochord and floor plate in caudal regions of the neural tube, and found that oligodendrocyte precursors did not appear at the ventricular surface where there was no floor plate. Moreover, oligodendrocytes did not develop in explant cultures of Sd/+ spinal cord in the absence of a floor plate. When a second notochord was grafted into an ectopic position dorsolateral to the endogenous notochord of a chicken embryo, an additional floor plate was induced along with an ectopic focus of oligodendrocyte precursors at the ventricular surface. Oligodendrocytes developed in explants of intermediate neural tube only when they were cocultured with fragments of notochord or in the presence of purified Sonic hedgehog (Shh) protein. Thus, signals from the notochord/floor plate, possibly involving Shh, are necessary and sufficient to induce the development of ventrally derived oligodendroglia. These signals appear to act by specifying the future fate(s) of neuroepithelial cells at the ventricular surface rather than by influencing the proliferation or differentiation of prespecified progenitor cells in the parenchyma of the cord.

Animals↗
PubMed1995

Protection by grafts of embryonal rat tissues (teratomas) against induction and transplantation of malignant tumors.

Clinical observations and experimental studies have shown that pregnancy may have inhibitory effects on tumor growth rather than invariably aggravate neoplastic disease as believed previously. It has been suggested that circulating factors of maternal or fetal origin may protect against tumor growth during pregnancy. The previously created experimental model of teratomas provides the means of having an adult animal bearing a permanent graft of embryonal tissues. To investigate the potential effects of embryonal factors on the growth of malignant neoplasms, rats carrying grafts of embryonal tissues were subjected to the induction or transplantation of carcinomas and lymphomas. Finely minced embryo tissues or cell suspensions injected in homologous rat recipients formed permanent benign teratomas composed of a variety of well differentiated tissues. One injection of N-methyl-N-nitrosourea, a potent carcinogen administered to all rats, induced fatal mammary adenocarcinoma in 50-60% of control rats but in none of the rats bearing a grafted teratoma. Transplantation of N-methyl-N-nitrosourea-induced mammary adenocarcinoma or Gross virus-induced lymphoma killed 100% of control rats but resulted in smaller, later appearing tumors in only 25-61% of teratoma-bearing rats. The present experiments showed that rats bearing grafts of embryonal tissues in the form of teratomas were partially or totally protected against the induction and transplantation of malignant tumors that killed 100% of controls. These results suggest that the embryonal tissues are a source of tumor-inhibitory factors, which may be a part of mechanisms controlling the growth and detecting the aberrations of embryonal tissues. Their identification and analysis may provide knowledge about embryonal growth and possibly about new substances with antineoplastic activity.

Animals↗
PubMed2000

Neural induction.

Development of neural fates from ectoderm is accompanied by the blockage of BMP signals at both protein and mRNA levels. Recent work has employed zebrafish, chick and mouse in addition to amphibians as models. Genetics has supplemented experimental embryology in enriching the understanding of the mechanism of neural induction and in posing new questions.

Animals↗
PubMedDate not supplied

Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins. I. Alpha-fetoprotein induction by ethionine.

The neoplastic cellular phenotype expresses many embryonic features. These features are believed to occur by derepression of embryonic genes during the carcinogenic process. A specific case is the ability of ethionine, a hepatocarcinogen, to induce an embryonic protein known as alpha-fetoprotein. A mechanism is proposed for this derepression process along with supporting evidence. It is hypothesized that the repressor protein for the alpha-fetoprotein gene must be modified (methylated) before it is functional and if for any reason this does not occur, alpha-fetoprotein will be produced. This simple theory can explain a variety of states of the liver cell in which alpha-fetoprotein is expressed namely i) fetal, ii) ethionine-treated, iii) neoplastic, and iv) tyrosinemic liver cells.

Animals↗
PubMed1996

Isolation and characterization of WNT8B, a novel human Wnt gene that maps to 10q24.

Wnt genes encode intercellular signalling molecules that play important roles in key processes of embryonic development such as mesoderm induction, specification of the embryonic axis, and patterning of the central nervous system, spinal cord, and limb. Multiple such genes are known to exist in each of several species that have been investigated, and they have been classified into various groups and subgroups on the basis of high sequence homology and common expression patterns. The vertebrate Wnt8 subfamily includes genes from Xenopus, zebrafish, and chicken, but, to date, no mammalian homologues have been described. We now report cloning and characterization of a novel human member of this family that we have termed WNT8B on the basis of the very high sequence similarity of the inferred protein to those encoded by the Xenopus and zebrafish Wnt8b genes. PCR typing of a human monochromosomal hybrid cell panel mapped the gene to chromosome 10, and FISH mapping provided a subchromosomal location at 10q24. Northern blotting and RT-PCR assays indicated that the WNT8B gene is expressed in several human tissues during fetal and adult stages.

Adult↗
PubMed1995

Sonic hedgehog induces the differentiation of ventral forebrain neurons: a common signal for ventral patterning within the neural tube.

The vertebrate hedgehog-related gene Sonic hedgehog (Shh) is expressed in ventral domains along the entire rostrocaudal length of the neural tube, including the forebrain. We show here that SHH induces the differentiation of ventral neuronal cell types in explants derived from prospective forebrain regions of the neural plate. Neurons induced in explants derived from both diencephalic and telencephalic levels of the neural plate express the LIM homeodomain protein Isl-1, and these neurons possess distinct identities that match those of the ventral neurons generated in these two subdivisions of the forebrain in vivo. A single inducing molecule, SHH, therefore appears to mediate the induction of distinct ventral neuronal cell types along the entire rostrocaudal extent of the embryonic central nervous system.

Activated-Leukocyte Cell Adhesion Molecule↗
PubMed2004

Heart induction: embryology to cardiomyocyte regeneration.

Developmental biologists have uncovered many of the signaling proteins that are required to recruit early embryonic cells to the myocardial lineage. A detailed understanding of their function should provide insights into the difficult task of inducing embryonic stem cells to develop cardiomyocyte precursors for cell-based therapies. These proteins may also prove to be useful to stimulate progenitor cells to differentiate into cardiomyocytes within the damaged heart.

Animals↗
PubMed1997

Mouse gastrulation: the formation of a mammalian body plan.

The process of gastrulation is a pivotal step in the formation of the vertebrate body plan. The primary function of gastrulation is the correct placement of precursor tissues for subsequent morphogenesis. There is now mounting evidence that the body plan is established through inductive interactions between germ layer tissues and by the global patterning activity emanating from embryonic organizers. An increasing number of mouse mutants have been described that have gastrulation defects, providing important insights into the molecular mechanisms that regulate this complex process. In this review, we explore the mouse embryo before and during gastrulation, highlighting its similarities with other vertebrate embryos and its unique characteristics.

Animals↗
PubMed1995

Induction of motor neurons by Sonic hedgehog is independent of floor plate differentiation.

BACKGROUND: The differentiation of floor plate cells and motor neurons in the vertebrate neural tube appears to be induced by signals from the notochord. The secreted protein encoded by the Sonic hedgehog (Shh) gene is expressed by axial midline cells and can induce floor plate cells in vivo and in vitro. Motor neurons can also be induced in vitro by cells that synthesize Sonic hedgehog protein (Shh). It remains unclear, however, if the motor-neuron-inducing activity of Shh depends on the synthesis of a distinct signaling molecule by floor plate cells. To resolve this issue, we have developed an in vitro assay which uncouples the notochord-mediated induction of motor neurons from floor plate differentiation, and have used this assay to examine whether Shh induces motor neurons in the absence of floor plate differentiation. RESULTS: Floor plate cells and motor neurons were induced in neural plate explants grown in contact with the notochord, but only motor neurons were induced when explants were separated from the notochord. COS cells transfected with Shh induced both floor plate cells and motor neurons when grown in contact with neural plate explants, whereas only motor neurons were induced when the explants were grown at a distance from Shh-transfected COS cells. Direct transfection of neural plate cells with an Shh-expression construct induced both floor plate cells and motor neurons, with motor neuron differentiation occurring prior to, or coincidentally with, floor plate differentiation. The induction of motor neurons appears, therefore, not to depend on floor plate differentiation. CONCLUSIONS: The induction of motor neurons by Shh does not depend on distinct floor-plate-derived signaling molecules. Shh can, therefore, initiate the differentiation of two cell types that are generated in the ventral region of the neural tube. These results show that the early development of motor neurons involves the inductive action of Shh, whereas the survival of motor neurons at later stages of embryonic development requires neurotrophic factors.

Animals↗
PubMed1999

Noggin is a mesenchymally derived stimulator of hair-follicle induction.

The induction of developmental structures derived from the ectoderm, such as the neural tube or tooth, occurs through neutralization of the inhibitory activity of members of the bone-morphogenetic protein (BMP) family by BMP antagonists. Here we show that, during hair-follicle development, the neural inducer and BMP-neutralizing protein Noggin is expressed in the follicular mesenchyme, that noggin-knockout mice show significant retardation of hair-follicle induction, and that Noggin neutralizes the inhibitory action of BMP-4 and stimulates hair-follicle induction in embryonic skin organ culture. As a crucial mesenchymal signal that stimulates hair-follicle induction, Noggin operates through antagonistic interactions with BMP-4, which result in upregulation of the transcription factor Lef-1 and the cell-adhesion molecule NCAM, as well as through BMP4-independent downregulation of the 75 kD neurotrophin receptor in the developing hair follicle.

Animals↗
PubMed1983

Inductive properties of fibroblastic cell cultures derived from rat intestinal mucosa on epithelial differentiation.

The present study represents a first attempt to elucidate the regulatory properties displayed by the non-epithelial portion of the intestinal mucosa, growing as fibroblasts in monolayer cultures. Thus, we compared the inductive action of 6-day suckling rat duodenal fibroblasts with that displayed by chick embryonic intestinal mesenchyme on the heterotypic cytodifferentiation of 5 1/2-day chick embryonic gizzard endoderm. The latter, isolated by 0.03% collagenase, was surrounded by intestinal intramucosal fibroblastic cell sheets. As control experiments, fibroblastic cells derived from the intestinal muscle or from 20-day fetal rat skin and lung were used. Every type of association was grafted into the coelomic cavity of 3-day chick embryos for 11 to 12 days, a system providing their vascularization and growth. The results clearly demonstrate that the mucosal fibroblastic cells of rat intestine were as potent as embryonic intestinal mesenchyme in inducing brush-border enzymes like sucrase and maltase, in conformity with an induced intestinal morphology. In contrast, the control fibroblastic cells were completely ineffective.

Alkaline Phosphatase↗
PubMed2001

Organizer and axes formation as a self-organizing process.

It is a widely held view that axis formation is based essentially on pre-localized determinants. However, the robustness of early development, the pattern regulation observed after experimental interferences and the existence of systems that don't require maternal determinants suggest that self-regulating pattern forming systems are also involved. A model is proposed that allows axes formation by a chain of reactions based on local self-enhancement and long-range inhibition. Their appropriate linkage ensures that the intermediary patterns emerge in the correct sequence and have the correct spatial relation to each other. Specifically, the model comprises the following events: the generation of a pole by a pattern-forming process, the formation of a second organizer eccentric to the pole (e.g. the Nieuwkoop center), the ecto-meso-endo subdivision, the generation of the Spemann-Mangold organizer with its anterior-posterior subdivision under the influence of the Nieuwkoop center, the conversion of the Spemann-Mangold organizer (a hot spot) into the notochord (a hot stripe), and the marking of the left side of the organism by a patterning reaction influenced by the midline. The pattern forming reactions do not depend on but can make use of maternally pre-localized determinants or asymmetries. Comparison with known genes and molecules reveals that many of the expected ingredients are present. Computer simulations show that the model accounts for many regulatory features reported in the literature. The computer simulations are available in an animated form at.

Animals↗
PubMed2001

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).

Activins↗
PubMed1995

Sonic hedgehog: a common signal for ventral patterning along the rostrocaudal axis of the neural tube.

The vertebrate hedgehog-related gene, sonic hedgehog, is expressed in ventral domains along the entire rostrocaudal length of the neural tube, including the forebrain. Shh induces the differentiation of ventral neuronal cell types in explants derived from prospective forebrain regions of the neural plate. Neurons induced in explants derived from diencephalic and telencephalic levels of the neural plate express the LIM homeodomain protein Islet-1, but these neurons possess distinct identities that match those of the ventral neurons normally generated in these two subdivisions of the forebrain. These results, together with other studies of neuronal differentiation at caudal levels of the neural tube, suggest that a single inducing molecule, Shh, mediates the induction of distinct ventral neuronal cell types along the entire rostrocaudal extent of the embryonic central nervous system.

Animals↗