Search PubMed⌕ Search

Biomedical subjects

I Greenwald

Publications and source records attributed to I Greenwald.

At least 55 records · Page 3Linked to original sources
PubMed1993

Genetic and phenotypic studies of hypomorphic lin-12 mutants in Caenorhabditis elegans.

The lin-12 gene of Caenorhabditis elegans is thought to encode a receptor for intercellular signals that specify certain cell fates during development. We describe several alleles of lin-12 that reduce but do not eliminate lin-12 activity (hypomorphic alleles). These alleles cause a novel egg-laying defective (Egl) phenotype in hermaphrodites as well as incompletely penetrant cell fate transformations seen with high penetrance in lin-12 null mutants. Characterization of the Egl phenotype revealed additional roles of lin-12 in the development of the egg-laying system that were not apparent from studying lin-12 null mutants: lin-12 activity is required for proper early vulval morphogenesis as well as for some unknown later aspect of egg-laying system development. Reversion of the Egl phenotype caused by one lin-12 hypomorphic allele was used to identify potential interacting genes as described in the accompanying paper.

Alleles↗
PubMed1993

Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans.

The lin-12 gene of Caenorhabditis elegans is thought to encode a receptor which mediates cell-cell interactions required to specify certain cell fates. Reversion of the egg-laying defective phenotype caused by a hypomorphic lin-12 allele identified rare extragenic suppressor mutations in five genes, sel-1, sel-9, sel-10, sel-11 and sel(ar40) (sel = suppressor and/or enhancer of lin-12). Mutations in each of these sel genes suppress defects associated with reduced lin-12 activity, and enhance at least one defect associated with elevated lin-12 activity. None of the sel mutations cause any obvious phenotype in a wild-type background. Gene dosage experiments suggest that sel-1 and sel(ar40) mutations are reduction-of-function mutations, while sel-9 and sel-11 mutations are gain-of-function mutations. sel-1, sel-9, sel-11 and sel(ar40) mutations do not suppress amorphic lin-12 alleles, while sel-10 mutations are able to bypass partially the requirement for lin-12 activity in at least one cell fate decision. sel-1, sel-9, sel-10, sel-11 and sel(ar40) mutations are also able to suppress the maternal-effect lethality caused by a partial loss-of-function allele of glp-1, a gene that is both structurally and functionally related to lin-12. These sel genes may therefore function in both lin-12 and glp-1 mediated cell fate decisions.

Alleles↗
PubMed1993

Two novel transmembrane protein tyrosine kinases expressed during Caenorhabditis elegans hypodermal development.

We describe our characterization of kin-15 and kin-16, a tandem pair of homologous Caenorhabditis elegans genes encoding transmembrane protein tyrosine kinases (PTKs) with an unusual structure: the predicted extracellular domain of each putative gene product is only about 50 amino acids, and there are no potential autophosphorylation sites in the C-terminal domain. Using lacZ fusions, we found that kin-15 and kin-16 both appear to be expressed during postembryonic development in the large hypodermal syncytium (hyp7) around the time that specific hypodermal cells fuse with hyp7. kin-15 and kin-16 were positioned on the genetic and physical maps, but extrachromosomal arrays containing wild-type kin-15 and/or kin-16 genes were unable to complement candidate lethal mutations. The results suggest that kin-15 and kin-16 may be specifically involved in cell-cell interactions regulating cell fusions that generate the hypodermis during postembryonic development.

Amino Acid Sequence↗
PubMed1993

glp-1 can substitute for lin-12 in specifying cell fate decisions in Caenorhabditis elegans.

Members of the lin-12/Notch gene family encode receptors for intercellular signals and are found throughout the animal kingdom. In many animals, the presence of at least two lin-12/Notch genes raises the issue of the significance of this duplication and divergence. In Caenorhabditis elegans, two lin-12/Notch genes, lin-12 and glp-1, encode proteins that are 50% identical, with different numbers of epidermal growth factor-like motifs in their extracellular domains. Many of the cell fate decisions mediated by lin-12 and glp-1 are distinct. Here, we express glp-1 protein under the control of lin-12 regulatory sequences in animals lacking endogenous lin-12 activity and find that glp-1 can substitute for lin-12 in mediating cell fate decisions. These results imply that the lin-12 and glp-1 proteins are biochemically interchangeable, sharing common ligand and effector proteins, and that the discrete lin-12 and glp-1 mutant phenotypes result from differential gene expression. In addition, these results suggest that the duplicate lin-12/Notch genes found in vertebrates may also be biochemically interchangeable.

Animals↗
PubMed1991

A genetic mosaic screen of essential zygotic genes in Caenorhabditis elegans.

We have devised a simple genetic mosaic screen, which circumvents the difficulties posed by phenotypic analysis of early lethal mutants, to analyze essential zygotic genes in Caenorhabditis elegans. The screen attempts to distinguish genes involved in cell type and/or lineage specific processes such as determination, differentiation or morphogenesis from genes involved in general processes such as intermediary metabolism by using the pattern of gene function to classify genes: genes required in one or a subset of early blastomeres may have specific functions, whereas genes required in all early blastomeres may have general functions. We found that 12 of 17 genes examined function in specific early blastomeres, suggesting that many zygotic genes contribute to specific early processes. We discuss the advantages and limitations of this screen, which is applicable to other regions of the C. elegans genome.

Alleles↗
PubMed1990

Analysis of gain-of-function mutations of the lin-12 gene of Caenorhabditis elegans.

Certain cell fate decisions are specified by cell-cell interactions during the development of the nematode Caenorhabditis elegans. For example, in a wild-type hermaphrodite gonad, two cells, Z1.ppp and Z4.aaa, have the potential to become the anchor cell (AC). Intercellular communication establishes their fates and ensures that only one cell becomes the AC, while the other becomes a ventral uterine precursor cell (VU). One component of this intercellular communication seems to be the 'AC-to-VU' signal from the presumptive AC that causes the other cell to become a VU. Genetic and developmental studies indicated that the lin-12 gene specifies the fates of Z1.ppp and Z4.aaa. Molecular studies suggest that lin-12 directly participates in their communications, perhaps acting as the receptor for the 'AC-to-VU' signal. Here, we report the molecular lesions associated with lin-12 gain-of-function mutations, cell isolation experiments, and genetic studies of an unusual lin-12 allele. These data suggest that self-association of the putative lin-12-encoded receptor leads to its activation, and that certain gain-of-function mutations result in ligand-independent activation.

Alleles↗
PubMed1990

Cell-cell interactions prevent a potential inductive interaction between soma and germline in C. elegans.

In each gonadal arm of wild-type C. elegans hermaphrodites, the somatic distal tip cell (DTC) maintains distal germline nuclei in mitosis, while proximal nuclei enter meiosis. We have identified two conditions under which a proximal somatic cell, the anchor cell (AC), inappropriately maintains proximal germline nuclei in mitosis: when defined somatic gonadal cells have been ablated in wild type, and in lin-12 null mutants. Laser ablations and mosaic analysis indicate that somatic gonadal cells neighboring the AC normally require lin-12 activity to prevent the inappropriate AC-germline interaction. The AC-germline interaction, like the DTC-germline interaction, requires glp-1 activity. In one model, we propose that the AC sends an intercellular signal intended to interact with the lin-12 product in somatic gonadal cells; when lin-12 activity is absent, the signal interacts instead with the related glp-1 product in germline. Our data illustrate the importance of mechanisms that prevent inappropriate interactions during development.

Animals↗
PubMed1989

glp-1 and lin-12, genes implicated in distinct cell-cell interactions in C. elegans, encode similar transmembrane proteins.

Genomic DNA closely related in sequence to lin-12, a gene that specifies certain cell fates during C. elegans development, was isolated from a C. elegans library by low stringency hybridization. DNA sequencing of genomic and cDNA clones predicts the new sequence to encode an integral membrane protein that shares three repeated amino acid sequence motifs with the lin-12 product and the Drosophila Notch product: an epidermal growth factor-like motif, the "lin-12/Notch Repeat," and a motif present in two yeast gene products that have cell cycle dependent functions. Austin and Kimble (see accompanying paper) present evidence that this sequence corresponds to glp-1, a gene implicated in cell-cell interactions distinct from those involving lin-12. Possible implications of the predicted structure of the glp-1 product with respect to these cell-cell interactions are discussed.

Animals↗
PubMed1989

Cell autonomy of lin-12 function in a cell fate decision in C. elegans.

The lin-12 gene of C. elegans encodes a predicted transmembrane protein that controls a decision by two cells, Z1.ppp and Z4.aaa, between the anchor cell (AC) and ventral uterine precursor cell (VU) fates. We performed laser ablation experiments to demonstrate that specification of the VU fate of Z1.ppp or Z4.aaa depends on an "AC-to-VU" signal from the presumptive AC. We generated genetic mosaics in which defined cells lacked lin-12 activity. By correlating the fates of Z1.ppp and Z4.aaa with the lin-12 genotype of nearly every cell in these mosaics, we conclude that lin-12 function is VU cell autonomous. We present a model in which lin-12 functions in the receiving mechanism for the "AC-to-VU" signal leading to the specification of the AC and VU fates of Z1.ppp and Z4.aaa.

Animals↗
PubMed1988

The Caenorhabditis elegans lin-12 gene encodes a transmembrane protein with overall similarity to Drosophila Notch.

The lin-12 gene seems to control certain binary decisions during Caenorhabditis elegans development, from genetic and anatomical studies of lin-12 mutants that have either elevated or reduced levels of lin-12 activity. We report here the complete DNA sequence of lin-12: 13.5 kilobases (kb) derived from genomic clones and 4.5 kb from complementary DNA clones. It is of interest that the predicted product is a putative transmembrane protein, given that many of the decisions controlled by lin-12 activity require cell-cell interactions for the correct choice of cell fate. In addition, the predicted lin-12 product may be classified into several regions, based on amino acid sequence similarities to other proteins. These include extensive overall sequence similarity to the Drosophila Notch protein, which also is involved in cell-cell interactions that specify cell fate; a repeated motif found in proteins encoded by the yeast cell-cycle control genes cdc10 (Schizosaccharomyces pombe) and SWI6 (Saccharomyces cerevisiae); and a repeated motif exemplified by epidermal growth factor, found in many mammalian proteins.

Animals↗
PubMed1988

A model of spatial localization and its application to strabismus.

Visually guided, spatially oriented behavior involves an ongoing integration of signals regarding the loci of the retinal images and the position and orientation of the eye. In the strabismic this requires an altered spatial metric resulting from a functional readaptation to avoid confusion and diplopia. A comparator mechanism for evaluating these two signals is presented. A case report using "disruptive" therapeutic procedures that deliberately alter the strabismic's visual-postural control system is presented. A treatment plan for altering the anomalous binocular link, a characteristic of the well adapted strabismic, is described and related to the comparator mechanism.

Adaptation, Physiological↗