H. Horvitz - Academia.edu (original) (raw)

Papers by H. Horvitz

Genetics, 1983

We have isolated 145 fertile mutants of C. elegans that are defective in egg laying and have char... more We have isolated 145 fertile mutants of C. elegans that are defective in egg laying and have characterized 59 of them genetically, behaviorally and pharmacologically. These 59 mutants define 40 new genes called egl, for egg-lay ing abnormal. Most of the other mutants are defective in previously identified genes. The egl mutants differ with respect to the severity of their egg-laying defects and the presence of behavioral or morphological pleiotropies. We have defined four distinct categories of mutants based on their responses to the pharmacological agents serotonin and imipramine, which stimulate egg laying by wild-type hermaphrodites. These drugs test the functioning of the vulva, the vulval and uterine muscles and the hermaphrodite-specific neurons (HSNs), which innervate the vulval muscles. Mutants representing 14 egl genes fail to respond to serotonin and to imipramine and are likely to be defective in the functioning of the vulva or the vulval and uterine muscles. Four mutants...

Developmental Biology, 1981

Journal of …, 2006

We show that the C. elegans gene unc-69 is required for axon outgrowth, guidance, fasciculation a... more We show that the C. elegans gene unc-69 is required for axon outgrowth, guidance, fasciculation and normal presynaptic organization. We identify UNC-69 as an evolutionarily conserved 108-amino-acid protein with a short coiled-coil domain. UNC-69 interacts physically with ...

Cell Differentiation and Development

Cell Biology International Reports

Nature, Jan 22, 2003

Defects in glycosaminoglycan biosynthesis disrupt animal development and can cause human disease.... more Defects in glycosaminoglycan biosynthesis disrupt animal development and can cause human disease. So far much of the focus on glycosaminoglycans has been on heparan sulphate. Mutations in eight squashed vulva (sqv) genes in Caenorhabditis elegans cause defects in cytokinesis during embryogenesis and in vulval morphogenesis during postembryonic development. Seven of the eight sqv genes have been shown to control the biosynthesis of the glycosaminoglycans chondroitin and heparan sulphate. Here we present the molecular identification and characterization of the eighth gene, sqv-5. This gene encodes a bifunctional glycosyltransferase that is probably localized to the Golgi apparatus and is responsible for the biosynthesis of chondroitin but not heparan sulphate. Our findings show that chondroitin is crucial for both cytokinesis and morphogenesis during C. elegans development.

Nature, Jan 23, 2000

The neurotransmitter and neuromodulator serotonin (5-HT) functions by binding either to metabotro... more The neurotransmitter and neuromodulator serotonin (5-HT) functions by binding either to metabotropic G-protein-coupled receptors (for example, 5-HT1, 5-HT2, 5-HT4 to 5-HT7), which mediate 'slow' modulatory responses through numerous second messenger pathways, or to the ionotropic 5-HT3 receptor, a non-selective cation channel that mediates 'fast' membrane depolarizations. Here we report that the gene mod-1 (for modulation of locomotion defective) from the nematode Caenorhabditis elegans encodes a new type of ionotropic 5-HT receptor, a 5-HT-gated chloride channel. The predicted MOD-1 protein is similar to members of the nicotinic acetylcholine receptor family of ligand-gated ion channels, in particular to GABA (gamma-aminobutyric acid)- and glycine-gated chloride channels. The MOD-1 channel has distinctive ion selectivity and pharmacological properties. The reversal potential of the MOD-1 channel is dependent on the concentration of chloride ions but not of cations. ...

Genes & development, 2000

One hallmark of apoptosis is the degradation of chromosomal DNA. We cloned the Caenorhabditis ele... more One hallmark of apoptosis is the degradation of chromosomal DNA. We cloned the Caenorhabditis elegans gene nuc-1, which is involved in the degradation of the DNA of apoptotic cells, and found that nuc-1 encodes a homolog of mammalian DNase II. We used the TUNEL technique to assay DNA degradation in nuc-1 and other mutants defective in programmed cell death and discovered that TUNEL labels apoptotic cells only during a transient intermediate stage. Mutations in nuc-1 allowed the generation of TUNEL-reactive DNA but blocked the conversion of TUNEL-reactive DNA to a subsequent TUNEL-unreactive state. Completion of DNA degradation did not occur in the absence of cell-corpse engulfment. Our data suggest that the process of degradation of the DNA of a cell corpse occurs in at least three distinct steps and requires activities provided by both the dying and the engulfing cell.

Development (Cambridge, England), 1999

The Caenorhabditis elegans hermaphrodite egg-laying system comprises several tissues, including t... more The Caenorhabditis elegans hermaphrodite egg-laying system comprises several tissues, including the uterus and vulva. lin-11 encodes a LIM domain transcription factor needed for certain vulval precursor cells to divide asymmetrically. Based on lin-11 expression studies and the lin-11 mutant phenotype, we find that lin-11 is also required for C. elegans uterine morphogenesis. Specifically, lin-11 is expressed in the ventral uterine intermediate precursor (pi) cells and their progeny (the utse and uv1 cells), which connect the uterus to the vulva. Like (pi) cell induction, the uterine lin-11 expression responds to the uterine anchor cell and the lin-12-encoded receptor. In wild type animals, the utse, which forms the planar process at the uterine-vulval interface, fuses with the anchor cell. We found that, in lin-11 mutants, utse differentiation was abnormal, the utse failed to fuse with the anchor cell and a functional uterine-vulval connection was not made. These findings indicate t...

Genetics, 1997

We identified and characterized 14 extragenic mutations that suppressed the dominant egg-laying d... more We identified and characterized 14 extragenic mutations that suppressed the dominant egg-laying defect of certain lin-12 gain-of-function mutations. These suppressors defined seven genes: sup-17, lag-2, sel-4, sel-5, sel-6, sel-7 and sel-8. Mutations in six of the genes are recessive suppressors, whereas the two mutations that define the seventh gene, lag-2, are semi-dominant suppressors. These suppressor mutations were able to suppress other lin-12 gain-of-function mutations. The suppressor mutations arose at a very low frequency per gene, 10-50 times below the typical loss-of-function mutation frequency. The suppressor mutations in sup-17 and lag-2 were shown to be rare non-null alleles, and we present evidence that null mutations in these two genes cause lethality. Temperature-shift studies for two suppressor genes, sup-17 and lag-2, suggest that both genes act at approximately the same time as lin-12 in specifying a cell fate. Suppressor alleles of six of these genes enhanced a ...

Nature, Jan 20, 1997

The Caenorhabditis elegans gene ced-9 prevents cells from undergoing programmed cell death and en... more The Caenorhabditis elegans gene ced-9 prevents cells from undergoing programmed cell death and encodes a protein similar to the mammalian cell-death inhibitor Bcl-2. We show here that the CED-9 protein is a substrate for the C. elegans cell-death protease CED-3, which is a member of a family of cysteine proteases first defined by CED-3 and human interleukin-1beta converting enzyme (ICE). CED-9 can be cleaved by CED-3 at two sites near its amino terminus, and the presence of at least one of these sites is important for complete protection by CED-9 against cell death. Cleavage of CED-9 by CED-3 generates a carboxy-terminal product that resembles Bcl-2 in sequence and in function. Bcl-2 and the baculovirus protein p35, which inhibits cell death in different species through a mechanism that depends on the presence of its cleavage site for the CED-3/ICE family of proteases, inhibit cell death additively in C. elegans. Our results indicate that CED-9 prevents programmed cell death in C. e...

Development (Cambridge, England), 1996

The C. elegans gene lin-26, which encodes a presumptive zinc-finger transcription factor, is requ... more The C. elegans gene lin-26, which encodes a presumptive zinc-finger transcription factor, is required for hypodermal cells to acquire their proper fates. Here we show that lin-26 is expressed not only in all hypodermal cells but also in all glial-like cells. During asymmetric cell divisions that generate a neuronal cell and a non-neuronal cell, LIN-26 protein is symmetrically segregated and then lost from the neuronal cell. Expression in glial-like cells (socket and sheath cells) is biologically important, as some of these neuronal support cells die or seem sometimes to be transformed to neuron-like cells in embryos homozygous for strong loss-of-function mutations. In addition, most of these glial-like cells are structurally and functionally defective in animals carrying the weak loss-of-function mutation lin-26(n156). lin-26 mutant phenotypes and expression patterns together suggest that lin-26 is required to specify and/or maintain the fates not only of hypodermal cells but also o...

Genetics, 1993

We have devised a method for selecting Caenorhabditis elegans mutants that execute feeding motion... more We have devised a method for selecting Caenorhabditis elegans mutants that execute feeding motions in the absence of food. One mutation isolated in this way is an allele of the gene unc-31, first discovered by S. Brenner in 1974, because of its effects on locomotion. We find that strong unc-31 mutations cause defects in four functions controlled by the nervous system. Mutant worms are lethargic, feed constitutively, are defective in egg-laying and produce dauer larvae that fail to recover. We discuss two extreme models to explain this pleiotropy: either unc-31 affects one or a few neurons that coordinately control several different functions, or it affects many neurons that independently control different functions.

Genetics, 1986

We have analyzed 31 mutations that have dominant effects on the behavior or morphology of the nem... more We have analyzed 31 mutations that have dominant effects on the behavior or morphology of the nematode Caenorhabditis elegans. These mutations appear to define 15 genes. We have studied ten of these genes in some detail and have been led to two notable conclusions. First, loss of gene function for four of these ten genes results in a wild-type phenotype; if these genes represent a random sample from the genome, then we would estimate that null mutations in about half of the genes in C. elegans would result in a nonmutant phenotype. Second, the dominant effects of mutations in nine of these ten genes are caused by novel gene functions, and in all nine cases the novel function is antagonized by the wild-type function.

Genetics, 1989

We previously identified Caenorhabditis elegans mutants in which certain of the six vulval precur... more We previously identified Caenorhabditis elegans mutants in which certain of the six vulval precursor cells adopt fates normally expressed by other vulval precursor cells. These mutants define genes that appear to function in the response to an intercellular signal that induces vulval development. The multivulva (Muv) phenotype of one such mutant, CB1322, results from an interaction between two unlinked mutations, lin-8(n111) II and lin-9(n112) III. In this paper, we identify 18 new mutations, which are alleles of eight genes, that interact with either lin-8(n111) or lin-9(n112) to generate a Muv phenotype. None of these 20 mutations alone causes any vulval cell lineage defects. The "silent Muv" mutations fall into two classes; hermaphrodites carrying a mutation of each class are Muv, while hermaphrodites carrying two mutations of the same class have a wild-type vulval phenotype. Our results indicate that the Muv phenotype of these mutants results from defects in two functi...

Genetics, 1991

After programmed cell death, a cell corpse is engulfed and quickly degraded by a neighboring cell... more After programmed cell death, a cell corpse is engulfed and quickly degraded by a neighboring cell. For degradation to occur, engulfing cells must recognize, phagocytose and digest the corpses of dying cells. Previously, three genes were known to be involved in eliminating cell corpses in the nematode Caenorhabditis elegans: ced-1, ced-2 and nuc-1. We have identified five new genes that play a role in this process: ced-5, ced-6, ced-7, ced-8 and ced-10. Electron microscopic studies reveal that mutations in each of these genes prevent engulfment, indicating that these genes are needed either for the recognition of corpses by other cells or for the initiation of phagocytosis. Based upon our study of double mutants, these genes can be divided into two sets. Animals with mutations in only one of these sets of genes have relatively few unengulfed cell corpses. By contrast, animals with mutations in both sets of genes have many unengulfed corpses. These observations suggest that these two ...