Biomedical subjects

D C Weinstein

Publications and source records attributed to D C Weinstein.

10 recordsLinked to original sources

PubMed2001

Src family kinase function during early Xenopus development.

The Src family kinase Laloo functions downstream of the fibroblast growth factor (FGF) receptor, as a component of a signaling pathway required for mesoderm formation. In this study, we first show that Laloo expression can mimic FGF function in a distinct context, suggesting that the Src-related kinases are general transducers of FGF signaling during development. We then characterize the role of the SH-PTP2 phosphatase, and of bone morphogenetic protein (BMP)-pathway signaling, in mesoderm induction by Laloo. Finally, we demonstrate that the mesoderm-inducing activity of the Src family kinases is not limited to Laloo, indicating a degree of functional overlap between members of this gene family during early vertebrate development.

Animals↗

PubMed2001

Is Chordin a morphogen?

Models employing gradients of diffusible morphogens are often invoked to explain regional specification in the early embryo. In these models, a concentration gradient of a secreted factor generates distinct cell fates, based on the differential response of cells to local concentrations of this morphogen. In recent years, there has been a great deal of focus on the factors involved in the dorsoventral patterning of the vertebrate mesoderm and ectoderm. Dorsoventral specification during amphibian gastrulation is regulated by the antagonistic actions of the Bone Morphogenetic Proteins (BMPs) and a number of dorsally expressed inhibitors, including the secreted factor, Chordin. In a recent paper, Blitz and colleagues explore the possibility that Chordin acts as a long-range factor in the amphibian gastrula embryo, to establish a functional gradient of BMP activity.

Animals↗

PubMed1999

Neural induction.

The formation of the vertebrate nervous system is initiated at gastrula stages of development, when signals from a specialized cluster of cells (the organizer) trigger neural development in the ectoderm. This process, termed neural induction, was first described in 1924 and stemmed from experiments on amphibia (Spemann & Mangold 1924). In recent years, the molecular mechanisms underlying neural induction in the amphibian have been elucidated. Surprisingly, neuralizing agents secreted by the organizer do not act via receptor-mediated signaling events; rather, these factors antagonize local epidermal inducers within the cells of the dorsal ectoderm and function to uncover the latent neural fate of these cells. Many of the recent advances in our understanding of vertebrate neural induction come from studies on the frog, Xenopus laevis. It is now clear that a blockade of signaling of the bone morphogenetic proteins (BMPs) during gastrula stages is sufficient to initiate neuralization of the ectoderm in this species. Thus this review first details our current understanding of neural induction, using the amphibian as a model. We then use data emerging from other systems to examine the extent to which the Xenopus studies can be applied to other vertebrate species. The initiation of the neurectoderm-specific gene expression program and subsequent steps in patterning and neuronal development are only touched on here. We focus primarily on the initial establishment of the neural fate in the vertebrate gastrula ectoderm.

Animals↗

PubMed1998

FGF-mediated mesoderm induction involves the Src-family kinase Laloo.

During embryogenesis, inductive interactions underlie the development of much of the body plan. In Xenopus laevis, factors secreted from the vegetal pole induce mesoderm in the adjacent marginal zone; members of both the transforming growth factor-beta (TGF-beta) and fibroblast growth factor (FGF) ligand families seem to have critical roles in this process. Here we report the identification and characterization of laloo, a novel participant in the signal transduction cascade linking extracellular, mesoderm-inducing signals to the nucleus, where alteration of cell fate is driven by changes in gene expression. Overexpression of laloo, a member of the Src-related gene family, in Xenopus embryos gives rise to ectopic posterior structures that frequently contain axial tissue. Laloo induces mesoderm in Xenopus ectodermal explants; this induction is blocked by reagents that disrupt the FGF signalling pathway. Conversely, expression of a dominant-inhibitory Laloo mutant blocks mesoderm induction by FGF and causes severe posterior truncations in vivo. This work provides the first evidence that a Src-related kinase is involved in vertebrate mesoderm induction.

Amino Acid Sequence↗

PubMed1997

Neural induction in Xenopus laevis: evidence for the default model.

At gastrulation, vertebrate ectoderm is competent to differentiate into either neural tissue or epidermis. Several soluble factors that can neuralize ectoderm in explant cultures have been isolated. Alternatively, neuralization can be achieved by dissociating the cells of the blastula ectoderm. These various treatments appear to neuralize by blocking or diluting out the action of an epidermal-inducing factor. Recent results demonstrate that bone morphogenetic protein 4 (BMP-4), a member of the transforming growth factor beta (TGF-beta) ligand superfamily, is a potent neural inhibitor and epidermal inducer and may represent the endogenous epidermal-inducing factor.

Activins↗

PubMed1997

Epidermal induction and inhibition of neural fate by translation initiation factor 4AIII.

Bone Morphogenetic Protein-4 (BMP-4) is a potent epidermal inducer and inhibitor of neural fate. We have used differential screening to identify genes involved in epidermal induction downstream of BMP-4 and report here evidence of a novel translational mechanism that regulates the division of the vertebrate ectoderm into regions of neural and epidermal fate. In dissociated Xenopus ectoderm, addition of ectopic BMP-4 leads to an increase in the expression of translation initiation factor 4AIII (eIF-4AIII), a divergent member of the eIF-4A gene family until now characterized only in plants. In the gastrula embryo, Xenopus eIF-4AIII (XeIF-4AIII) expression is elevated in the ventral ectoderm, a site of active BMP signal transduction. Moreover, overexpression of XeIF-4AIII induces epidermis in dissociated cells that would otherwise adopt a neural fate, mimicking the effects of BMP-4. Epidermal induction by XeIF-4AIII requires both an active BMP signaling pathway and an extracellular intermediate. Our results suggest that XeIF-4AIII can regulate changes in cell fate through selective mRNA translation. We propose that BMPs and XeIF-4AIII interact through a positive feedback loop in the ventral ectoderm of the vertebrate gastrula.

Amino Acid Sequence↗

PubMed1996

Embryonic expression of eph signalling factors in Xenopus.

Cellular communication in the developing embryo is mediated by receptor-ligand interactions at the cell surface. Receptor protein tyrosine kinases (RTKs) have been shown to play a critical role in the development of the vertebrate embryo. The eph receptors are a large subclass of RTKs for which a corresponding ligand family has only recently been described. The restricted expression patterns of several eph receptors imply roles for these molecules in early vertebrate development. We have isolated both a ligand of the eph ligand family (ELF), that we have named XELF-a, and an eph-related receptor, XE10, the likely homolog of the murine eck/Sek-2 receptor. At least two forms of the XELF-a transcript are present in the developing embryo. A truncated form of the XELF-a ligand, XELF-á, is the first ELF ligand isolated that lacks both the membrane-spanning and membrane-anchoring motifs conserved among this family, suggesting that ELF ligands can function as fully soluble molecules in vivo. XELF-a and XE10 are expressed maternally and throughout early embryogenesis, while XELF-á is only expressed zygotically. The dynamic expression patterns of these signalling molecules, in both mesoderm and neurectoderm, suggest that they may play a role in the patterning of the early vertebrate embryo.

Amino Acid Sequence↗

PubMed1994

Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos.

Expression of HNF-4, a transcription factor in the steroid hormone receptor superfamily, is detected only in the visceral endoderm of mouse embryos during gastrulation and is expressed in certain embryonic tissues from 8.5 days of gestation. To examine the role of HNF-4 during embryonic development, we disrupted the gene in embryonic stem cells and found that the homozygous loss of functional HNF-4 protein was an embryonic lethal. Cell death was evident in the embryonic ectoderm at 6.5 days when these cells normally initiate gastrulation. As assessed by expression of Brachyury and HNF-3 beta, primitive streak formation and initial differentiation of mesoderm do occur, but with a delay of approximately 24 h. Development of embryonic structures is severely impaired. These results demonstrate that the expression of HNF-4 in the visceral endoderm is essential for embryonic ectoderm survival and normal gastrulation.

Animals↗

PubMed1994

The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo.

HNF-3 beta, a transcription factor of the winged-helix family, is expressed in embryonic and adult endoderm and also in midline cells of the node, notochord, and floor plate in mouse embryos. To define the function of HNF-3 beta, a targeted mutation in the HNF-3 beta locus was generated by homologous recombination in embryonic stem cells. Mice lacking HNF-3 beta die by embryonic day (E) 10-11. Mutant embryos examined from E6.5 to E9.5 do not form a distinct node and lack a notochord. In addition, mutant embryos show marked defects in the organization of somites and neural tube that may result from the absence of the notochord. The neural tube of mutant embryos exhibits overt anteroposterior polarity but lacks a floor plate and motor neurons. Endodermal cells are present but fail to form a gut tube in mutant embryos. These studies indicate that HNF-3 beta has an essential role in the development of axial mesoderm in mouse embryos.

Animals↗

PubMed1994

Expression of transcription factor HNF-4 in the extraembryonic endoderm, gut, and nephrogenic tissue of the developing mouse embryo: HNF-4 is a marker for primary endoderm in the implanting blastocyst.

The expression of HNF-4 (hepatocyte nuclear factor 4) mRNA in postimplantation mouse embryos was analyzed by in situ hybridization. Expression was found in the primary endoderm at embryonic day 4.5 and was restricted to the columnar visceral endoderm cells of the yolk sac from day 5.5 to day 8.5. HNF-4 mRNA was first detected in embryonic tissues at day 8.5, in the liver diverticulum and the hindgut. At later times HNF-4 transcripts were observed in the mesonephric tubules, pancreas, stomach, and intestine and, still later, in the metanephric tubules of the developing kidney. This expression pattern suggests that HNF-4 has a role in the earliest stages of murine postimplantation development as well as in organogenesis.

Animals↗