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Biomedical subjects

J Gerhart

Publications and source records attributed to J Gerhart.

At least 19 recordsLinked to original sources
PubMed1999

Hepatocyte growth factor/scatter factor promotes a switch from E- to N-cadherin in chick embryo epiblast cells.

Epiblast cells downregulate E-cadherin and upregulate N-cadherin as they ingress through the primitive streak and when placed in culture. The factors that promote the alteration in cadherin expression during gastrulation are unknown. The effects of hepatocyte growth factor/scatter factor (HGF/SF) on cadherin expression were tested in cultures of prestreak epiblast cells. HGF/SF decreased the expression of E-cadherin and increased the percentage of cells with N-cadherin and sarcomeric myosin. Cells with N-cadherin but not E-cadherin differentiated into skeletal muscle. HGF/SF also stimulated proliferation and the formation of cellular aggregates. Sensitivity to HGF/SF in vitro depended on the original position of cells within the epiblast. More cells from the lateral epiblast switched cadherins and proliferated in response to HGF/SF than medial epiblast cells. HGF/SF may affect gastrulation by altering cadherin expression, modulating cell adhesion, and stimulating proliferation within the epiblast.

Animals↗
PubMed1998

Evolvability.

Evolvability is an organism's capacity to generate heritable phenotypic variation. Metazoan evolution is marked by great morphological and physiological diversification, although the core genetic, cell biological, and developmental processes are largely conserved. Metazoan diversification has entailed the evolution of various regulatory processes controlling the time, place, and conditions of use of the conserved core processes. These regulatory processes, and certain of the core processes, have special properties relevant to evolutionary change. The properties of versatile protein elements, weak linkage, compartmentation, redundancy, and exploratory behavior reduce the interdependence of components and confer robustness and flexibility on processes during embryonic development and in adult physiology. They also confer evolvability on the organism by reducing constraints on change and allowing the accumulation of nonlethal variation. Evolvability may have been generally selected in the course of selection for robust, flexible processes suitable for complex development and physiology and specifically selected in lineages undergoing repeated radiations.

Animals↗
PubMed1998

The role of stably committed and uncommitted cells in establishing tissues of the somite.

Somites are blocks of embryonic mesoderm tissue that give rise to skeletal muscle, cartilage, and other connective tissues. The development of different tissues within the somite is influenced by adjacent structures, in particular, the neural tube and notochord. Results of experiments performed in vivo and in vitro suggest that somites contain populations of cells stably programmed to undergo either skeletal myogenesis or chondrogenesis and a population uncommitted to either pathway. The fate of the uncommitted cells would depend on a transfer of information from the committed cells. Communication between committed and uncommitted cells is regulated by cell and tissue interactions that either activate or inhibit this process.

Animals↗
PubMed1997

N-cadherin promotes the commitment and differentiation of skeletal muscle precursor cells.

Cells with the potential to form skeletal muscle are present in the chick embryo prior to gastrulation. Muscle differentiation begins after gastrulation within the somites. The role of cadherin-mediated adhesion in the commitment and differentiation of skeletal muscle precursor cells was examined by analyzing the expression of cell-cell adhesion molecules in cultures of epiblast, segmental plate, and somite cells and by determining the effects of adhesion-perturbing antibodies on the accumulation of MyoD and sarcomeric myosin. Cultured primitive streak stage epiblast cells downregulate E-cadherin and upregulate N-cadherin. This switch in cadherin expression also occurs in vivo as epiblast cells enter the primitive streak. Although MyoD protein is present in cells with N- or E-cadherin, only cells with N-cadherin differentiate into skeletal muscle. In contrast to the primitive streak stage epiblast cells, prestreak epiblast cells maintain the expression of E-cadherin in vitro. While the majority of prestreak cells contain MyoD, only a few synthesize myosin. Treatment of primitive streak stage epiblast cells with function-perturbing antibodies to N-cadherin resulted in an inhibition of myosin accumulation and a decrease in the percentage of cells with MyoD. Segmental plate and somite cells are similar to primitive streak stage epiblast cells in that most differentiated into skeletal muscle when cultured in serum-free medium. While function-perturbing antibodies to N-cadherin inhibited the accumulation of myosin in these mesoderm cells, the number of MyoD positive cells was unaffected in somite cultures and only partially reduced in segmental plate cultures. These results suggest that N-cadherin-mediated cell-cell adhesion is involved in both the commitment of muscle precursors and their terminal differentiation.

Animals↗
PubMed1997

Formation and function of Spemann's organizer.

The organizer is formed in an equatorial sector of the blastula stage amphibian embryo by cells that have responded to two maternal agents: a general mesoendoderm inducer (involving the TFG-beta signaling pathway) and a dorsal modifier (probably involving the Wnt signaling pathway). The meso-endoderm inducer is secreted by most vegetal cells, those containing maternal materials that had been localized in the vegetal hemisphere of the oocyte during oogenesis. As a consequence of the inducer's distribution and action, the competence domains of prospective ectoderm, mesoderm, and endoderm are established in an animal-to-vegetal order in the blastula. The dorsal modifier signal is secreted by a sector of cells of the animal and vegetal hemispheres on one side of the blastula. These cells contain maternal materials transported there in the first cell cycle from the vegetal pole of the egg along microtubules aligned by cortical rotation. The Nieuwkoop center is the region of blastula cells secreting both maternal signals, and hence specifying the organizer in an equatorial sector. Final steps of organizer formation at the late blastula or early gastrula stage may involve locally secreted zygotic signals as well. At the gastrula stage, the organizer secretes a variety of zygotic proteins that act as antagonists to various members of the BMP and Wnt families of ligands, which are secreted by cells of the competence domains surrounding the organizer. BMPs and Wnts favor ventral development, and cells near the organizer are protected from these agents by the organizer's inducers. The nearby cells are derepressed in their inherent capacity for dorsal development, which is apparent in the neural induction of the ectoderm, dorsalization of the mesoderm, and anteriorization of the endoderm. The organizer also engages in extensive specialized morphogenesis, which brings it within range of responsive cell groups. It also self-differentiates to a variety of axial tissues of the body.

Amphibians↗
PubMed1996

Skeletal myogenesis: the preferred pathway of chick embryo epiblast cells in vitro.

The epiblast layer of the chick embryo gives rise to all embryonic tissues. In vitro analyses were carried out to determine whether epiblast cells could form skeletal muscle prior to entry into the primitive streak. Epiblasts were separated from the mesoderm, hypoblast, and primitive streak, dissociated to produce a single cell suspension, and plated at high density. Myogenesis began on the first day in culture, and by the fifth day most cells had differentiated into skeletal muscle. Some cells differentiated without replicating. MyoD messenger RNA was present in epiblast tissue and translated in practically all cells in culture. Cells from regions of the epiblast which do not form muscle later in the embryo did so in vitro. Epiblasts cultured for 2 days as an intact epithelium, or in the presence of the mesoderm and hypoblast, did not undergo myogenesis. These findings demonstrate that myogenic potential is wide-spread within the primitive streak stage epiblast, and that muscle differentiation, which occurs relatively autonomously in culture, can be prevented by cell and tissue interactions.

Animals↗
PubMed1989

Cortical rotation of the Xenopus egg: consequences for the anteroposterior pattern of embryonic dorsal development.

We first review cortical-cytoplasmic rotation, a microtubule-mediated process by which the Xenopus egg, like other amphibian eggs, transforms its polarized cylindrical symmetry into bilateral symmetry within the first cell cycle after fertilization. This transformation, the earliest of many steps leading to dorsal development, involves the displacement of the egg's cortex relative to its cytoplasmic core by 30 degrees in an animal-vegetal direction. As rotation is progressively reduced by microtubule-depolymerizing agents, embryos develop with body axes progressively deleted for dorsal structures at the anterior end. With no rotation, ventralized embryos are formed. In an effort to comprehend this progressive effect on embryonic organization, we go on to review subsequent developmental process depending on rotation, and we propose, with evidence, that reduced rotation leads to a reduced number of vegetal dorsalizing cells, which induce during the blastula stage a Spemann organizer region of smaller than normal size. The reduced organizer then promotes a reduced amount of cell rearrangement (morphogenesis) at gastrulation. Reduced morphogenesis seems the proximate cause of the incompleteness of axial pattern, as shown further by the fact that embryos that are normal until the gastrula stage, if exposed to inhibitors of morphogenesis, develop body axes that are progressively less complete in their anterior dorsal organization the earlier their gastrulation had been blocked. We discuss why axial pattern might depend systematically on morphogenesis.

Animals↗
PubMed1985

M-phase promoting factors from eggs of Xenopus laevis.

When an M-phase promoting factor (MPF) is injected into Xenopus oocytes, which are naturally arrested at the G2/prophase boundary, it induces rapid entry of the cells into M-phase. MPF is present in late G2 and in M-phase of a variety of cell types, such as Xenopus eggs (naturally arrested in M), cleaving embryos, yeast, HeLa, and CHO cultures. MPF has been purified approximately 50-fold from eggs. It is stabilized by gamma-thio-ATP and by phosphoprotein phosphatase inhibitors. It runs as a protein of approximately 100 kd size on gel filtration. Oocytes contain a precursor of MPF, which is activated by post-translational means when a small amount of purified MPF is injected into the cell. Thus, MPF appears to be an auto-activating cytoplasmic trigger of M-phase. At anaphase of the cell cycle, MPF is inactivated due to the appearance of an 'anti-MPF' activity. Monoclonal antibodies have been prepared to partially purified MPF stabilized by gamma-thio-ATP, and several preparations which inactivate MPF were obtained. The antibodies are directed against thio-phosphate groups carried by a set of proteins including MPF. This indicates that MPF is present in our active preparations as a thio-phosphoprotein. These and other data suggest that MPF is normally activated in the cell cycle by a phosphorylation reaction.

Animals↗
PubMed1984

Dynorphin A: inhibitory effect on other opiate ligand bindings in the mouse brain.

The opioid peptide dynorphin A antagonizes morphine-induced analgesia in vivo and inhibits opiate binding in vitro, although most of it is rapidly degraded under both conditions. The inhibitory effect was present even in tissue treated in vivo with dynorphin A and assayed in vitro without it. Shorter fragments of this peptide lacked these effects, indicating that the apparent potency did not result from a metabolite. Na+ ion specifically reversed both agonist and antagonist binding from in vitro inhibition by dynorphin A. These results are discussed in terms of current opioid receptor theories.

Animals↗
PubMed1984

Dynorphin1-13: interaction with other opiate ligand bindings in vitro.

Dynorphin1-13 is a potent inhibitor of electrically-induced contractions in the guinea pig ileum, where it has the properties of kappa-(ethylketocyclazocine) type opioids. In the brain, however, it has no analgesic potency, yet inhibits that induced by morphine. To gain further insight into its mechanism of action in the latter system, we tested its ability to compete for the binding of several opiates to brain membranes in vitro. Dynorphin1-13 inhibited the binding of all ligands examined, including dihydromorphine, D-Ala2-D-Leu5-enkephalin, ethylketacyclazocine (EKC) and naloxone. In all cases, it reduced the number of high affinity sites and, in the case of EKC, it also increased the Kd. We conclude that the mechanism of dynorphin inhibition is not simple rapidly reversible competition and is certainly not identical with respect to all opiate ligands.

Animals↗
PubMed1984

Effects of chlordecone exposure on brain neurotransmitters: possible involvement of the serotonin system in chlordecone-elicited tremor.

The purpose of this study was to correlate the chlordecone-elicited tremor activity with alterations of brain neurotransmitters. A single injection of chlordecone (80 mg/kg, ip) significantly increased the brain levels of 5-hydroxyindoleacetic acid (5-HIAA) but did not affect the concentrations of dopamine, dihydroxphenylacetic acid, aspartate, taurine, glutamate, glycine, and gamma-aminobutyric acid (GABA). There was a dose- and time-related correlation between the increases in striatal 5-HIAA levels and tremor after chlordecone treatment. A subsequent study with pargyline indicated that the increase in striatal 5-HIAA level represented an increase in the turnover of serotonin. This study plus the previous finding that pizotifen (BC-105), a serotonin receptor blocker, attenuated chlordecone-elicited tremor strongly suggests a possible involvement of the serotonin system in mediating the tremor elicited by this insecticide.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Cell cycle dynamics of an M-phase-specific cytoplasmic factor in Xenopus laevis oocytes and eggs.

We have examined the regulation of maturation-promoting factor (MPF) activity in the mitotic and meiotic cell cycles of Xenopus laevis eggs and oocytes. To this end, we developed a method for the small scale extraction of eggs and oocytes and measured MPF activity in extracts by a dilution end point assay. We find that in oocytes, MPF activity appears before germinal vesicle breakdown and then disappears rapidly at the end of the first meiotic cycle. In the second meiotic cycle, MPF reappears before second metaphase, when maturation arrests. Thus, MPF cycling coincides with the abbreviated cycles of meiosis. When oocytes are induced to mature by low levels of injected MPF, cycloheximide does not prevent the appearance of MPF at high levels in the first cycle. This amplification indicates that an MPF precursor is present in the oocyte and activated by posttranslational means, triggered by the low level of injected MPF. Furthermore, MPF disappears approximately on time in such oocytes, indicating that the agent for MPF inactivation is also activated by posttranslational means. However, in the absence of protein synthesis, MPF never reappears in the second meiotic cycle. Upon fertilization or artificial activation of normal eggs, MPF disappears from the cytoplasm within 8 min. For a period thereafter, the inactivating agent remains able to destroy large amounts of MPF injected into the egg. It loses activity just as endogenous MPF appears at prophase of the first mitotic cycle. The repeated reciprocal cycling of MPF and the inactivating agent during cleavage stages is unaffected by colchicine and nocodazole and therefore does not require the effective completion of spindle formation, mitosis, or cytokinesis. However, MPF appearance is blocked by cycloheximide applied before mitosis; and MPF disappearance is blocked by cytostatic factor. In all these respects, MPF and the inactivating agent seem to be tightly linked to, and perhaps participate in, the cell cycle oscillator previously described for cleaving eggs of Xenopus laevis (Hara, K., P. Tydeman, and M. Kirschner, 1980, Proc. Natl. Acad. Sci. USA, 77:462-466).

Animals↗