Wnt Signaling and an APC-Related Gene Specify Endoderm in Early C. elegans Embryos

Rocheleau, Christian E.; Downs, William D.; Lin, Rueyling; Wittmann, Claudia; Bei, Yanxia; Cha, Yoon‐Hee; Ali, Mussa; Priess, James R; Mello, Craig C.

doi:10.1016/s0092-8674(00)80531-0

Cited by 612 publications

(621 citation statements)

References 52 publications

(18 reference statements)

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“…RNA-mediated interference is a method for reducing endogenous gene activity in C. elegans (22,23 The fact that we see hop-1 RNA-mediated interference phenotypes only when sel-12 activity is reduced suggests that hop-1 and sel-12 are functionally redundant. The simplest interpretation of this apparent functional redundancy is that, in some cases, HOP-1 and SEL-12 may be expressed and may function within the same cells.…”

Section: Discussionmentioning

confidence: 94%

“…RNA-mediated interference is a widely used method for reducing gene activity in C. elegans and has been shown in many cases to give a phenotype similar to null alleles (22,23). Both antisense and sense RNAs appear to have the same effect (22).…”

Section: Resultsmentioning

confidence: 99%

“…Both antisense and sense RNAs appear to have the same effect (22). RNA-mediated interference appears to cause targeted suppression of the corresponding gene in the germ line of injected hermaphrodites, so that progeny display phenotypes associated with loss of gene function (22,23). Although the penetrance of these phenotypes is incomplete, the expressivity can be high.…”

Section: Resultsmentioning

confidence: 99%

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HOP-1, a Caenorhabditis elegans presenilin, appears to be functionally redundant with SEL-12 presenilin and to facilitate LIN-12 and GLP-1 signaling

Greenwald

1997

Proc. Natl. Acad. Sci. U.S.A.

155

127

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Mutant presenilins have been found to cause Alzheimer disease. Here, we describe the identification and characterization of HOP-1, a Caenorhabditis elegans presenilin that displays much more lower sequence identity with human presenilins than does the other C. elegans presenilin, SEL-12. Despite considerable divergence, HOP-1 appears to be a bona fide presenilin, because HOP-1 can rescue the egg-laying defect caused by mutations in sel-12 when hop-1 is expressed under the control of sel-12 regulatory sequences. HOP-1 also has the essential topological characteristics of the other presenilins. Reducing hop-1 activity in a sel-12 mutant background causes synthetic lethality and terminal phenotypes associated with reducing the function of the C. elegans lin-12 and glp-1 genes. These observations suggest that hop-1 is functionally redundant with sel-12 and underscore the intimate connection between presenilin activity and LIN-12͞ Notch activity inferred from genetic studies in C. elegans and mammals.Genetic linkage studies have identified a number of loci associated with familial Alzheimer disease (1). Two of these loci encode related multipass transmembrane proteins, presenilins 1 and 2 (PS1 and PS2). Mutations in the genes encoding PS1 and PS2 loci are dominant and fully penetrant for early onset Alzheimer disease (2-4). The presenilins are ubiquitously expressed (3, 4) and found in conjunction with intracellular membranes (5). However, the normal role of presenilins, and the mechanism by which mutant presenilins cause Alzheimer disease, are not known.Genetic studies in simple organisms offer a powerful approach to understanding the normal role of presenilins. The Caenorhabditis elegans sel-12 gene encodes a protein that displays about 50% amino acid sequence identity to PS1 and PS2 (6). Genetic analysis established that reducing or eliminating sel-12 activity causes an egg-laying defective (Egl) phenotype, and that sel-12 activity facilitates the activity of LIN-12 and GLP-1, two receptors of the LIN-12͞Notch family (6). SEL-12 appears to be a bona fide presenilin, because human PS1 and PS2 can rescue the Egl phenotype of a sel-12 mutant (7). Furthermore, the membrane topology of SEL-12 and PS1 appears to be similar (8-10). In addition to the functional and structural similarities, expression studies indicate that SEL-12 and human presenilins are expressed throughout development in many different cell types (3, 4, 7).We have identified another candidate C. elegans presenilin based on predicted amino acid sequence by searching the genomic sequence database (11,12). Here, we show that this gene, which we have named hop-1 (hop ϭ homolog of presenilin), encodes a functional presenilin, by demonstrating that HOP-1 can rescue the egg-laying defect of a sel-12 mutant. We also show that HOP-1 has characteristic features of presenilin membrane topology. Finally, we show that reducing hop-1 activity in a sel-12 mutant background results in novel phenotypes, suggesting that hop-1 and sel-12 are functionally redundant.

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Section: Discussionmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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HOP-1, a Caenorhabditis elegans presenilin, appears to be functionally redundant with SEL-12 presenilin and to facilitate LIN-12 and GLP-1 signaling

Greenwald

1997

Proc. Natl. Acad. Sci. U.S.A.

155

127

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“…elegans has five Wnts [CWN-1, CWN-2, EGL-20, LIN-44 and MOM-2 (Shackleford et al, 1993;Herman et al, 1995;Thorpe et al, 1997;Whangbo and Kenyon, 1999)], four Frizzleds [CFZ-2, LIN-17, MIG-1 and MOM-5 (Sawa et al, 1996;Rocheleau et al, 1997;Zinovyeva and Forrester, 2005;Pan et al, 2006)] and a single Ryk, LIN-18 (Inoue et al, 2004). Wnt signaling establishes the polarity of asymmetric cell divisions, determines cell fates and guides cell migrations (Korswagen, 2002;Herman, 2002).…”

Section: Introductionmentioning

confidence: 99%

Wnt signaling establishes anteroposterior neuronal polarity and requires retromer inC. elegans

2006

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Secreted Wnt proteins influence neural connectivity by regulating axon guidance, dendritic morphogenesis and synapse formation. We report a new role for Wnt and Frizzled proteins in establishing the anteroposterior polarity of the mechanosensory neurons ALM and PLM in C. elegans. Disruption of Wnt signaling leads to a complete inversion of ALM and PLM polarity: the anterior process adopts the length, branching pattern and synaptic properties of the wild-type posterior process, and vice versa. Different but overlapping sets of Wnt proteins regulate neuronal polarity in different body regions. Wnts act directly on PLM via the Frizzled LIN-17. In addition, we show that they are needed for axon branching and anteriorly directed axon growth. We also find that the retromer, a conserved protein complex that mediates transcytosis and endosome-to-Golgi protein trafficking, plays a key role in Wnt signaling. Deletion mutations of retromer subunits cause ALM and PLM polarity, and other Wnt-related defects. We show that retromer protein VPS-35 is required in Wnt-expressing cells and propose that retromer activity is needed to generate a fully active Wnt signal.

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“…In one report, RNAi silences genes 10-fold more efficiently than antisense RNA alone. 10 To avoid nonspecific gene silencing induced by longer double-stranded RNA, small interfering RNA (siRNA), a duplex of 21-23 nucleotides, has been used as a mediator to degrade target mRNA. 11 Once inside the cell, siRNA is incorporated into an RNA-induced silence complex (RISC), a protein-RNA complex resulting in unwinding and strand separation of the RNA duplex.…”

mentioning

confidence: 99%

Small interfering RNA targeting Raf-1 inhibits tumor growth in vitro and in vivo

Leng

Mixson

2005

Cancer Gene Ther

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Raf-1 is a cytosolic serine-threonine kinase that plays an important role in tumor cell growth, proliferation, and apoptosis. Upregulated Raf-1 activity has also been implicated in tumor angiogenesis and metastasis. In this study, we used a promising new RNA interfering technology that targets Raf-1 mRNA both in vitro and in vivo. We initially found that Raf-1 siRNA markedly reduced Raf-1 mRNA in MDA-MB-435 cells in vitro by approximately 75% compared to control siRNA treatment groups. Raf-1 siRNA also reduced cell number by inducing apoptosis in a number of cell lines including HUVEC, MDA-MB-435, and C6 cells. After screening several histidine-lysine polymers in complex with Raf-1 siRNA to reduce tumor growth, we further evaluated the efficacy of this siRNA in complex with the optimal histidine-lysine carrier to reduce the tumor growth in vivo. MDA-MB-435 xenografts treated by intratumoral injections of Raf-1 siRNA were significantly reduced compared with the control groups. By the fourth measurement, tumor growth was reduced by nearly 60% in the Raf-1 siRNA treatment group compared with the untreated group (Po.02). Taken together, our data provide evidence that Raf-1 siRNA may be an effective strategy for reducing tumor growth.

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Wnt Signaling and an APC-Related Gene Specify Endoderm in Early C. elegans Embryos

Cited by 612 publications

References 52 publications

HOP-1, a Caenorhabditis elegans presenilin, appears to be functionally redundant with SEL-12 presenilin and to facilitate LIN-12 and GLP-1 signaling

HOP-1, a Caenorhabditis elegans presenilin, appears to be functionally redundant with SEL-12 presenilin and to facilitate LIN-12 and GLP-1 signaling

Wnt signaling establishes anteroposterior neuronal polarity and requires retromer inC. elegans

Small interfering RNA targeting Raf-1 inhibits tumor growth in vitro and in vivo

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