A Limited Number of Caenorhabditis elegans Genes Are Readily Mutable to Dominant, Temperature-Sensitive Maternal-Effect Embryonic Lethality

Abstract Dominant gain-of-function mutations can give unique insights into the study of gene function. In addition, gain-of-function mutations, unlike loss-of-function alleles, are not biased against the identification of genetically redundant loci. To identify novel genetic functions active during Caenorhabditis elegans embryogenesis, we have collected a set of dominant temperature-sensitive maternal-effect embryonic lethal mutations. In a previous screen, we isolated eight such mutations, distributed among six genes. In the present study, we describe eight new dominant mutations that identify only three additional genes, yielding a total of 16 dominant mutations found in nine genes. Therefore, it appears that a limited number of C. elegans genes mutate to this phenotype at appreciable frequencies. Five of the genes that we identified by dominant mutations have loss-of-function alleles. Two of these genes may lack loss-of-function phenotypes, indicating that they are nonessential and so may represent redundant loci. Loss-of-function mutations of three other genes are associated with recessive lethality, indicating nonredundancy.

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Maternal-effect lethal mutations on linkage group II of Caenorhabditis elegans.

Genetics ◽

10.1093/genetics/120.4.977 ◽

1988 ◽

Vol 120 (4) ◽

pp. 977-986

Author(s):

K J Kemphues ◽

M Kusch ◽

N Wolf

Keyword(s):

Caenorhabditis Elegans ◽

Linkage Group ◽

Maternal Effect ◽

Essential Genes ◽

The Other ◽

C Elegans ◽

Lethal Mutations ◽

Embryonic Lethal ◽

Embryonic Lethal Mutations ◽

F1 Progeny

Abstract We have analyzed a set of linkage group (LG) II maternal-effect lethal mutations in Caenorhabditis elegans isolated by a new screening procedure. Screens of 12,455 F1 progeny from mutagenized adults resulted in the recovery of 54 maternal-effect lethal mutations identifying 29 genes. Of the 54 mutations, 39 are strict maternal-effect mutations defining 17 genes. These 17 genes fall into two classes distinguished by frequency of mutation to strict maternal-effect lethality. The smaller class, comprised of four genes, mutated to strict maternal-effect lethality at a frequency close to 5 X 10(-4), a rate typical of essential genes in C. elegans. Two of these genes are expressed during oogenesis and required exclusively for embryogenesis (pure maternal genes), one appears to be required specifically for meiosis, and the fourth has a more complex pattern of expression. The other 13 genes were represented by only one or two strict maternal alleles each. Two of these are identical genes previously identified by nonmaternal embryonic lethal mutations. We interpret our results to mean that although many C. elegans genes can mutate to strict maternal-effect lethality, most genes mutate to that phenotype rarely. Pure maternal genes, however, are among a smaller class of genes that mutate to maternal-effect lethality at typical rates. If our interpretation is correct, we are near saturation for pure maternal genes in the region of LG II balanced by mnC1. We conclude that the number of pure maternal genes in C. elegans is small, being probably not much higher than 12.

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Mutations affecting the meiotic and mitotic divisions of the early Caenorhabditis elegans embryo.

Genetics ◽

10.1093/genetics/126.3.593 ◽

1990 ◽

Vol 126 (3) ◽

pp. 593-605 ◽

Cited By ~ 5

Author(s):

P E Mains ◽

K J Kemphues ◽

S A Sprunger ◽

I A Sulston ◽

W B Wood

Keyword(s):

Caenorhabditis Elegans ◽

Maternal Effect ◽

Mutant Gene ◽

Temperature Sensitive ◽

Loss Of Function ◽

Gain Of Function ◽

Lethal Mutations ◽

Cell Embryo ◽

New Gene ◽

The One

Abstract We describe interactions between maternal-effect lethal mutations in four genes of Caenorhabditis elegans whose products appear to be involved in the meiotic and mitotic divisions of the one-cell embryo. Mitosis is disrupted by two dominant temperature-sensitive gain-of-function maternal-effect lethal mutations, mei-1(ct46) and mel-26(ct61), and by recessive loss-of-function maternal-effect lethal mutations of zyg-9. The phenotypic defects resulting from these mutations are similar. Doubly mutant combinations show a strong enhancement of the maternal-effect lethality under semipermissive conditions, suggesting that the mutant gene products interact. We isolated 15 dominant suppressors of the gain-of-function mutation mei-1(ct46). Thirteen of these suppressors are apparently intragenic, but 11 of them suppress in trans as well as cis. Two extragenic suppressors define a new gene, mei-2. The suppressor mutations in these two genes also result in recessive maternal-effect lethality, but with meiotic rather than mitotic defects. Surprisingly, most of these suppressors are also able to suppress mel-26(ct61) in addition to mei-1(ct46). The products of the four genes mei-1, mei-2, zyg-9 and mel-26 could be responsible for some of the specialized features that distinguish the meiotic from the mitotic divisions in the one-cell embryo.

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A Survey of New Temperature-Sensitive, Embryonic-Lethal Mutations in C. elegans: 24 Alleles of Thirteen Genes

PLoS ONE ◽

10.1371/journal.pone.0016644 ◽

2011 ◽

Vol 6 (3) ◽

pp. e16644 ◽

Cited By ~ 40

Author(s):

Sean M. O'Rourke ◽

Clayton Carter ◽

Luke Carter ◽

Sara N. Christensen ◽

Minh P. Jones ◽

...

Keyword(s):

Temperature Sensitive ◽

C Elegans ◽

Lethal Mutations ◽

Embryonic Lethal ◽

Embryonic Lethal Mutations

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A novel dominant transformer allele of the sex-determining gene her-1 of Caenorhabditis elegans.

Genetics ◽

10.1093/genetics/120.1.145 ◽

1988 ◽

Vol 120 (1) ◽

pp. 145-157

Author(s):

C Trent ◽

W B Wood ◽

H R Horvitz

Keyword(s):

Caenorhabditis Elegans ◽

Sexual Identity ◽

Temperature Sensitive ◽

Dominant Allele ◽

Loss Of Function ◽

Gain Of Function ◽

C Elegans

Abstract We have characterized a novel dominant allele of the sex-determining gene her-1 of Caenorhabditis elegans. This allele, called n695, results in the incomplete transformation of XX animals into phenotypic males. Previously characterized recessive her-1 alleles transform XO animals into phenotypic hermaphrodites. We have identified five new recessive her-1 mutations as intragenic suppressors of n695. Three of these suppressors are weak, temperature-sensitive alleles. We show that the recessive her-1 mutations are loss-of-function alleles, and that the her-1(n695) mutation results in a gain-of-function at the her-1 locus. The existence of dominant and recessive alleles that cause opposite phenotypic transformations demonstrates that the her-1 gene acts to control sexual identity in C. elegans.

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Dominant maternal-effect mutations causing embryonic lethality in Caenorhabditis elegans.

Genetics ◽

10.1093/genetics/125.2.351 ◽

1990 ◽

Vol 125 (2) ◽

pp. 351-369 ◽

Cited By ~ 3

Author(s):

P E Mains ◽

I A Sulston ◽

W B Wood

Keyword(s):

Caenorhabditis Elegans ◽

Maternal Effect ◽

Gene Dosage ◽

Recessive Mutation ◽

Dominant Male ◽

Temperature Sensitive ◽

Male Mating ◽

Loss Of Function ◽

Dominant Mutant ◽

Embryonic Viability

Abstract We undertook screens for dominant, temperature-sensitive, maternal-effect embryonic-lethal mutations of Caenorhabditis elegans as a way to identify certain classes of genes with early embryonic functions, in particular those that are members of multigene families and those that are required in two copies for normal development. The screens have identified eight mutations, representing six loci. Mutations at three of the loci result in only maternal effects on embryonic viability. Mutations at the remaining three loci cause additional nonmaternal (zygotic) effects, including recessive lethality or sterility and dominant male mating defects. Mutations at five of the loci cause visible pregastrulation defects. Three mutations appear to be allelic with a recessive mutation of let-354. Gene dosage experiments indicate that one mutation may be a loss-of-function allele at a haploin sufficient locus. The other mutations appear to result in gain-of-function "poison" gene products. Most of these become less deleterious as the relative dosage of the corresponding wild-type allele is increased; we show that relative self-progeny viabilities for the relevant hermaphrodite genotypes are generally M/+/+ greater than M/+ greater than M/M/+ greater than M/Df greater than M/M, where M represents the dominant mutant allele.

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The let-60 locus controls the switch between vulval and nonvulval cell fates in Caenorhabditis elegans.

Genetics ◽

10.1093/genetics/126.4.899 ◽

1990 ◽

Vol 126 (4) ◽

pp. 899-913 ◽

Cited By ~ 9

Author(s):

M Han ◽

R V Aroian ◽

P W Sternberg

Keyword(s):

Caenorhabditis Elegans ◽

Genetic Interaction ◽

Dominant Negative ◽

Loss Of Function ◽

Wild Type ◽

Gain Of Function ◽

Recessive Lethal ◽

Lethal Mutations ◽

Anchor Cell ◽

Inductive Signal

Abstract During induction of the Caenorhabditis elegans hermaphrodite vulva by the anchor cell of the gonad, six multipotent vulval precursor cells (VPCs) have two distinct fates: three VPCs generate the vulva and the other three VPCs generate nonspecialized hypodermis. Genes that control the fates of the VPCs in response to the anchor cell signal are defined by mutations that cause all six VPCs to generate vulval tissue (Multivulva or Muv) or that cause all six VPCs to generate hypodermis (Vulvaless or Vul). Seven dominant Vul mutations were isolated as dominant suppressors of a lin-15 Muv mutation. These mutations are dominant alleles of the gene let-60, previously identified only by recessive lethal mutations. Our genetic studies of these dominant Vul recessive lethal mutations, recessive lethal mutations, intragenic revertants of the dominant Vul mutations, and the closely mapping semi-dominant multivulva lin-34 mutations suggest that: (1) loss-of-function mutations of let-60 are recessive lethal at a larval stage, but they also cause a Vul phenotype if the lethality is rescued maternally by a lin-34 gain-of-function mutation. (2) The dominant Vul alleles of let-60 are dominant negative mutations whose gene products compete with wild-type activity. (3) lin-34 semidominant Muv alleles are either gain-of-function mutations of let-60 or gain-of-function mutations of an intimately related gene that elevates let-60 activity. We propose that let-60 activity controls VPC fates. In a wild-type animal, reception by a VPC of inductive signal activates let-60, and it generates into a vulval cell type; in absence of inductive signal, let-60 activity is low and the VPC generates hypodermal cells. Our genetic interaction studies suggest that let-60 acts downstream of let-23 and lin-15 and upstream of lin-1 and lin-12 in the genetic pathway specifying the switch between vulval and nonvulval cell types.

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Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

Nature Communications ◽

10.1038/s41467-020-20269-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Mercedes M. Pérez-Jiménez ◽

José M. Monje-Moreno ◽

Ana María Brokate-Llanos ◽

Mónica Venegas-Calerón ◽

Alicia Sánchez-García ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Caenorhabditis Elegans ◽

Protein Aggregation ◽

Steroid Hormones ◽

Sensory Neurons ◽

Environmental Cues ◽

Steroid Sulfatase ◽

Loss Of Function ◽

C Elegans ◽

Age Related

AbstractAging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer’s disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.

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A Cuticle Collagen Encoded by the lon-3 Gene May Be a Target of TGF-β Signaling in Determining Caenorhabditis elegans Body Shape

Genetics ◽

10.1093/genetics/162.4.1631 ◽

2002 ◽

Vol 162 (4) ◽

pp. 1631-1639

Author(s):

Yo Suzuki ◽

Gail A Morris ◽

Min Han ◽

William B Wood

Keyword(s):

Caenorhabditis Elegans ◽

Body Shape ◽

Small Body ◽

Dependent Manner ◽

Loss Of Function ◽

Cellular Mechanisms ◽

C Elegans ◽

Gene Expression Analyses ◽

Dose Dependent

Abstract The signaling pathway initiated by the TGF-β family member DBL-1 in Caenorhabditis elegans controls body shape in a dose-dependent manner. Loss-of-function (lf) mutations in the dbl-1 gene cause a short, small body (Sma phenotype), whereas overexpression of dbl-1 causes a long body (Lon phenotype). To understand the cellular mechanisms underlying these phenotypes, we have isolated suppressors of the Sma phenotype resulting from a dbl-1(lf) mutation. Two of these suppressors are mutations in the lon-3 gene, of which four additional alleles are known. We show that lon-3 encodes a collagen that is a component of the C. elegans cuticle. Genetic and reporter-gene expression analyses suggest that lon-3 is involved in determination of body shape and is post-transcriptionally regulated by the dbl-1 pathway. These results support the possibility that TGF-β signaling controls C. elegans body shape by regulating cuticle composition.

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Identification and Characterization of Genes That Interact With lin-12 in Caenorhabditis elegans

Genetics ◽

10.1093/genetics/147.4.1675 ◽

1997 ◽

Vol 147 (4) ◽

pp. 1675-1695 ◽

Cited By ~ 2

Author(s):

Frans E Tax ◽

James H Thomas ◽

Edwin L Ferguson ◽

H Robert Horvitzt

Keyword(s):

Cell Fate ◽

Low Frequency ◽

Signal Transduction Pathway ◽

Temperature Shift ◽

Egg Laying ◽

Null Alleles ◽

Temperature Sensitive ◽

Loss Of Function ◽

Gain Of Function ◽

Suppressor Mutations

Abstract 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-l7, 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 sup1 7 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, sup1 7and lag-2, suggest that both genes act at approximately the same time as lin-12in specifying a cell fate. Suppressor alleles of six of these genes enhanced a temperature-sensitive loss-of-function allele of glp-1, a gene related to lin-12 in structure and function. Our analysis of these suppressors suggests that the majority of these genes are part of a shared lin-12/glp-1 signal transduction pathway, or act to regulate the expression or stability of lin-12 and glp-1.

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glp-3 Is Required for Mitosis and Meiosis in the Caenorhabditis elegans Germ Line

Genetics ◽

10.1093/genetics/145.1.111 ◽

1997 ◽

Vol 145 (1) ◽

pp. 111-121 ◽

Cited By ~ 1

Author(s):

Lisa C Kadyk ◽

Eric J Lambie ◽

Judith Kimble

Keyword(s):

Caenorhabditis Elegans ◽

Germ Cells ◽

Germ Line ◽

Stem Cell Population ◽

Phenotypic Characterization ◽

Loss Of Function ◽

Dapi Staining ◽

Cell Cycles ◽

C Elegans ◽

Mitosis And Meiosis

The germ line is the only tissue in Caenorhabditis elegans in which a stem cell population continues to divide mitotically throughout life; hence the cell cycles of the germ line and the soma are regulated differently. Here we report the genetic and phenotypic characterization of the glp-3 gene. In animals homozygous for each of five recessive loss-of-function alleles, germ cells in both hermaphrodites and males fail to progress through mitosis and meiosis, but somatic cells appear to divide normally. Germ cells in animals grown at 15° appear by DAPI staining to be uniformly arrested at the G2/M transition with <20 germ cells per gonad on average, suggesting a checkpoint-mediated arrest. In contrast, germ cells in mutant animals grown at 25° frequently proliferate slowly during adulthood, eventually forming small germ lines with several hundred germ cells. Nevertheless, cells in these small germ lines never undergo meiosis. Double mutant analysis with mutations in other genes affecting germ cell proliferation supports the idea that glp-3 may encode a gene product that is required for the mitotic and meiotic cell cycles in the C. elegans germ line.

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