Biomedical subjects

M Sym

Publications and source records attributed to M Sym.

6 recordsLinked to original sources

PubMed2000

A model for niemann-pick type C disease in the nematode Caenorhabditis elegans.

Niemann-Pick type C (NP-C) disease is a progressive neurodegenerative disorder characterized by the inappropriate accumulation of unesterified cholesterol in lysosomes [1]. NP-C patients show various defects including hepatosplenomegaly, ataxia, dystonia and dementia. Most cases of NP-C are associated with inactivating mutations of the NPC1 gene [2], which encodes a protein implicated in the retrograde transport of sterols and other cargo from lysosomes [3]. Furthermore, localization of the NPC1 protein to lysosomal/endosomal compartments is essential for proper transport [4]. To create a model of NP-C disease in a simple, genetically tractable organism, we generated deletion mutations in two Caenorhabditis elegans homologs of the human NPC1 gene, designated npc-1 and npc-2. Animals mutant for npc-1 developed slowly, laid eggs prematurely, and were hypersensitive to cholesterol deprivation. Furthermore, npc-1; npc-2 double-mutant animals inappropriately formed dauer larvae under favorable growth conditions. These phenotypes in C. elegans provide a model system for both genetic and chemical suppressor screening that could identify promising drug targets and leads for NP-C disease.

Amino Acid Sequence↗

PubMed1999

MIG-13 positions migrating cells along the anteroposterior body axis of C. elegans.

The C. elegans Q neuroblasts and their descendants migrate along the anteroposterior (A/P) body axis to positions that are not associated with any obvious landmarks. We find that a novel protein, MIG-13, is required to position these cells correctly. MIG-13 is a transmembrane protein whose expression is restricted to the anterior and central body regions by Hox gene activity. MIG-13 functions non-cell autonomously within these regions to promote migration toward the anterior: loss of mig-13 activity shifts the Q descendants toward the posterior, whereas increasing the level of MIG-13 shifts them anteriorly in a dose-dependent manner. Our findings suggest that MIG-13 is a component of a global A/P migration system, and that the level of MIG-13 determines where along the body axis these migrating cells stop.

Amino Acid Sequence↗

PubMed1995

Roles for two RecA homologs in promoting meiotic chromosome synapsis.

Previous studies have shown that the RAD51 and DMC1 genes of Saccharomyces cerevisiae encode homologs of the Escherichia coli RecA strand exchange enzyme. Results presented here demonstrate that the dmc1 and rad51 mutants undergo nearly complete chromosome synapsis, but synaptonemal complex formation is delayed substantially compared with wild type. In the zip1 mutant, chromosomes are paired homologously, but not synapsed, and the protein backbones (axial elements) of each pair of chromosomes are connected intimately to each other at a few sites referred to herein as axial associations. dmc1 zip1 and rad51 zip1 double mutants assemble axial elements that are not obviously associated, demonstrating that the Dmc1 and Rad51 proteins are required to establish or stabilize axial associations. We propose that axial associations serve to promote meiotic chromosome synapsis and that the absence of these associations accounts for the delayed and inefficient synapsis observed in dmc1 and rad51 strains. During meiosis in haploid yeast, chromosome synapsis takes place between nonhomologous chromosome segments. In a zip1 haploid, axial associations are not apparent, suggesting that these associations depend on interactions between homologous sequences.

Alleles↗

PubMed1995

Zip1-induced changes in synaptonemal complex structure and polycomplex assembly.

The yeast Zip1 protein is a component of the synaptonemal complex (SC), which is an elaborate macromolecular structure found along the lengths of chromosomes during meiosis. Mutations that increase the length of the predicted coiled coil region of the Zip1 protein show that Zip1 influences the width of the SC. Overexpression of the ZIP1 gene results in the formation of two distinct types of higher order structures that are found in the nucleus, but not associated with chromatin. One of these structures resembles the polycomplexes that have been observed in many organisms and are thought to be aggregates of SC components. The second type of structure, which we have termed "networks," does not resemble any previously identified SC-related structure. Assembly of both polycomplexes and networks can occur independently of the Hop1 or Red1 protein, which are thought to be SC components. Our results demonstrate that Zip1 is a structural component of the central region of the SC. More specifically, we speculate that Zip1 is a component of the transverse filaments that lie perpendicular to the long axis of the complex.

Chromosomes, Fungal↗

PubMed1994

Crossover interference is abolished in the absence of a synaptonemal complex protein.

In the zip1 mutant, meiotic chromosomes fail to synapse, owing to the absence of a structural component of the synaptonemal complex (SC). This mutant has been analyzed for the ability to carry out several functions that have been proposed for the SC. The data presented show that the zip1 mutation does not affect chiasma function and confers only modest defects in meiotic recombination and sister chromatid cohesion. In contrast, crossover interference is completely abolished in the absence of Zip1. These data are the first to establish a molecular link between cytological observations of the SC and the genetic phenomenon of interference.

Chromosomes↗

PubMed1993

ZIP1 is a synaptonemal complex protein required for meiotic chromosome synapsis.

ZIP1 is a novel meiosis-specific gene required for chromosome synapsis and cell cycle progression in S. cerevisiae. zip1 strains undergo homologous chromosome pairing, but are defective in synaptonemal complex (SC) formation. The zip1 mutation confers a uniform arrest in meiosis prior to the first division. zip1 strains display nearly wild-type levels of commitment to meiotic recombination; however, mature reciprocal recombinants are not formed until cells are released from meiotic arrest by return to growth medium. DNA sequence analysis of ZIP1 reveals structural homology to a number of proteins containing coiled coils. Immunofluorescence experiments using anti-ZIP1 antibodies demonstrate that the ZIP1 protein localizes to synapsed meiotic chromosomes but not to unsynapsed axial elements. Taken together, these data suggest that ZIP1 is a component of the central region of the SC. We propose a model in which ZIP1 acts as a molecular zipper to bring homologous chromosomes in close apposition.

Amino Acid Sequence↗