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1 Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan
2 CREST, Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan
3 Department of Physiology, Tokyo Women’s Medical University School of Medicine, Tokyo 162-8666, Japan
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Abstract |
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Introduction |
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The popular models for intra-Golgi transport are the stable compartments model and cisternal maturation model (Pelham & Rothman 2000). A fundamental difference between these two models is the differential movement of resident and cargo proteins. In the stable compartments model, each cisterna is a long-lived structure that retains a characteristic set of Golgi-resident proteins, and anterograde vesicles carry the newly synthesized proteins forward from cis to trans (Rothman & Wieland 1996; Schekman & Orci 1996; Orci et al. 1997). By contrast, the cisternal maturation model proposes that biosynthetic proteins move through the Golgi stack passively as the cisternae move forward, while resident proteins are recycled to younger cisternae by retrograde transport to establish differential concentrations across the stack (Glick et al. 1997; Mironov et al. 1997; Allan & Balch 1999). These two models are not mutually exclusive and their pathways may operate simultaneously (Rabouille & Klumperman 2005). Recently, the cisternal maturation model was proved using video microscopy of living cells in yeast (Losev et al. 2006; Matsuura-Tokita et al. 2006). In the cisternal maturation model, the coat-protein I (COPI)-coated vesicles move in a retrograde fashion and function as a retrieving device that is used by Golgi-resident proteins such as mannosidase II, a glycosidase of the medial Golgi stack, to maintain their specific and differential localization over the Golgi apparatus (Rabouille & Klumperman 2005).
The primary role for COPI in retrograde transport has been verified biochemically, genetically and morphologically (Allan & Balch 1999). COPI vesicles have been shown to concentrate Golgi processing enzymes (Love et al. 1998; Lanoix et al. 1999; Martinez-Menargues et al. 2001; Gilchrist et al. 2006) and to possess their own unique soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, GS28 (Orci et al. 2000; Gilchrist et al. 2006). GS28 (Golgi SNARE of 28 kDa, also known as GOS28) is thought to mediate fusion of COPI vesicles at the Golgi complex, functioning as a vesicle membrane SNARE (v-SNARE) (Nagahama et al. 1996; Subramaniam et al. 1996; Hay et al. 1998). In an in vitro analysis, GS28 was preferentially incorporated into COPI-derived vesicles (Nagahama et al. 1996). At the cellular level, GS28 is involved in intra-Golgi transport together with a vesicle-tethering factor, the conserved oligomeric Golgi (COG) complex in COPI-mediated retrograde trafficking (Ram et al. 2002; Suvorova et al. 2002; Xu et al. 2002; Oka et al. 2004; Tai et al. 2004; Shestakova et al. 2006; Vasile et al. 2006). Yeast genetic studies also suggest that a yeast GS28 homologue, Gos1p, is involved in intra-Golgi transport (McNew et al. 1998; Bensen et al. 2001). However, the in vivo functions of GS28, and consequently, the role of intra-Golgi retrograde transport in animal development is largely unknown.
A search of the database for sequences similar to human GS28 found homologues in various animals including the simple multicellular organism, C. elegans. In this study, we generated deletion mutants of C. elegans GS28 to elucidate the physiological functions of GS28 in vivo. We also performed an RNAi modifier screen using GS28 mutants and found that another Golgi-localized v-SNARE, Ykt6, functions cooperatively with GS28 in cell proliferation and/or differentiation of stem cell-like epithelial cells (seam cells). Furthermore, we showed that GS28 and Ykt6 act redundantly for the proper expression of Golgi-resident proteins in C. elegans.
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Results |
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A database search of C. elegans genome sequence revealed the presence of one GS28 homologue named gosr-1 (Golgi snap receptor complex member-1). The gosr-1 gene product (GOSR-1) consists of 234 amino acid residues and shows 34% and 35% identity with human and mouse GS28 respectively. GOSR-1 possesses helix motifs (Fig. 1a, black lines), a SNARE domain (Fig. 1a, blue line) and a transmembrane domain (Fig. 1a, green line) in a similar manner to other SNARE proteins. Furthermore, like GS28 in other species, C. elegans GOSR-1 has a unique sequence ‘LRKxARxxENxxDxKLV’ at the N-terminus (Fig. 1a, red line).
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gosr-1 mutants show defects in ray formation
Expression analysis suggested that gosr-1 functions in seam cells from the embryo to larval stages, and acts mainly in intestinal cells after development into adults. To investigate the functional roles of GS28 in vivo, we isolated a gosr-1 deletion allele, designated gosr-1(tm2800), by polymerase chain reaction (PCR)-based deletion screening of TMP-UV-mutagenized libraries (Gengyo-Ando & Mitani 2000). The tm2800 allele deleted 323 bp (2nd to 5th exons) which includes the SNARE helix motifs (Fig. 2a), suggesting that the product is completely functionless. The gosr-1(tm2800) homozygous hermaphrodites had no defects under a stereomicroscope except a slight reduction in brood size at adulthood (Table S1 in Supporting Information). However, when we generated a male population, we noticed that the gosr-1(tm2800) males had an abnormal tail structure.
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gosr-1 and ykt-6 cooperatively function in normal ray formation in C. elegans
During male development, gosr-1p::GFP was also expressed in seam cells including V5, V6 and T (data not shown). In gosr-1 mutant males, the penetrance of missing ray phenotype of R7–R9 was incomplete and formation of rays R1–R6 was not affected. These observations suggest that other molecule(s) function redundantly with gosr-1. To identify genes which functionally compensate for gosr-1, we conducted an enhancer screen for RNAi clones that cause severer defects in the gosr-1 mutant background than in the wild-type background. We tested 74 genes whose homologues are known to be involved in intracellular vesicle transport (see Table S2 in Supporting Information and Experimental procedures), and found that knockdown of ykt-6 (B0361.10) by feeding RNAi remarkably enhanced embryonic lethality (Emb) in the gosr-1 mutant background (Fig. 3a–e: 94.6% Emb in gosr-1 mutants vs. 1.1% Emb in wild-type worms). ykt-6 encodes a protein with structural similarity to mammalian Ykt6, a v-SNARE protein localized in Golgi apparatus. To examine the contribution of ykt-6 to ray formation in post-embryonic development, hatching embryos were subjected to ykt-6 RNAi. We found that knockdown of ykt-6 from the early larval stage induced morphological ray defects; 75% of gosr-1(tm2800) mutants showed the missing ray phenotype while only 27% of wild-type worms exhibited ray defects under the same RNAi conditions (Fig. 3f–h). Most gosr-1(tm2800); ykt-6(RNAi) worms exhibited a strong missing ray phenotype in which all rays were lost (Fig. 3g). We could not examine ray formation in ykt-6 deletion mutants (tm3575), because they exhibited larval arrest (Fig. S2a–d in Supporting Information). We also could not analyze gosr-1(tm2800) ykt-6(tm3575) double mutants as the genetic position of ykt-6 is very close to that of gosr-1 (–0.76 and –0.75 on chromosome III respectively). Taken together, these data indicate that two Golgi SNAREs, gosr-1 and ykt-6, cooperatively function in embryonic development and normal ray formation in C. elegans.
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In hermaphrodites, seam cells also divide asymmetrically in a stem cell-like manner producing an anterior daughter cell that fuses with an epithelial cell (hyp7), and a posterior daughter cell that assumes the seam cell fate again (Sulston & Horvitz 1977; Fig. S1b in Supporting Information). To examine the cellular basis of seam cell-derived ray defects, we further analyzed the number of seam cells in hermaphrodites using the seam cell marker (scm::gfp, transgene wIs51). Wild-type adult hermaphrodites usually contain 16 seam cells on each side of the worm at the end of development (Fig. 4a). They derived from the 10 blast cells (H0-2, V1-6 and T) (Fig. S1b in Supporting Information). Both gosr-1(tm2800) and ykt-6(RNAi) hermaphrodites contained 16 seam cells [average numbers, 16.0 (n = 30) and 15.9 (n = 32) respectively] (Fig. 4b,c). However, gosr-1(tm2800); ykt-6(RNAi) hermaphrodites contained significantly fewer seam cells [average number, 14.1 (n = 31)] (Fig. 4d). These results indicate that gosr-1 and ykt-6 are cooperatively required for either seam cell division or seam cell differentiation. As mentioned above, in males, posterior seam cells undergo stem cell-like divisions and differentiation to produce sensory rays. The reduced seam cell number in gosr-1(tm2800); ykt-6(RNAi) hermaphrodites suggests that the failure of seam cell proliferation or differentiation is the basis of the missing ray phenotype observed in gosr-1(tm2800); ykt-6(RNAi) males.
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GS28 is the most prominent SNARE protein in COPI-coated vesicle (Gilchrist et al. 2006). COPI vesicles move in a retrograde fashion and function as a retrieving device that is used by Golgi-resident proteins to maintain their specific and differential localization over the Golgi stack (Rabouille & Klumperman 2005). To elucidate the effects of gosr-1 and/or ykt-6 inhibition on Golgi-resident proteins, we examined the expression level of mannosidase II, a glycosidase localized in the medial Golgi stack. We expressed a C. elegans alpha-mannosidase II::GFP fusion protein in wild-type and gosr-1(tm2800) worms under the control of the intestine-specific vha-6 promoter (pwIs503[vha-6p::mans::gfp], see Experimental procedures; Rolls et al. 2002; Chen et al. 2006; Samuelson et al. 2007) because both gosr-1 and ykt-6 are expressed in intestine at the adult stage (Fig. 1g and Fig. S3 in Supporting Information). As shown in Fig. 5a–d, mannosidase II::GFP expressed in the intestinal cells was slightly reduced in gosr-1(tm2800) and ykt-6(RNAi) adult worms, whereas the GFP level was strikingly reduced in gosr-1(tm2800); ykt-6(RNAi) worms. A western blot analysis also revealed that the amount of mannosidase II::GFP was remarkably reduced in gosr-1(tm2800); ykt-6(RNAi) animals (Fig. 5e). vha-6 mRNA level did not change in gosr-1(tm2800); ykt-6(RNAi) animals, indicating that vha-6 promoter was not affected in these worms (data not shown). These data suggest that Golgi-resident proteins are destabilized in gosr-1(tm2800) and ykt-6(RNAi) worms and that two Golgi SNAREs, gosr-1 and ykt-6 cooperatively act for the proper expression of Golgi-resident proteins in C. elegans.
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Discussion |
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Expression of gosr-1 is restricted to certain types of epithelial cells, such as seam cells and intestinal cells (Fig. 1b–g), whereas ykt-6 is expressed in more tissues than gosr-1, including the ventral nerve cord, some neuronal cells in the head region and epithelial cells (Fig. S3 in Supporting Information). On the other hand, deletion of each gene results in different phenotypes with respect to C. elegans development: gosr-1 mutants are viable and fertile (Table S1 in Supporting Information), while all of the ykt-6 homozygous mutants show larval arrest and never produce progeny (Fig. S2b–d in Supporting Information). These observations suggest that ykt-6 is the predominant Golgi SNARE in C. elegans development.
GS28 is efficiently packaged into COPI-coated vesicles that mediate intra-Golgi retrograde transport (Nagahama et al. 1996; Orci et al. 2000; Gilchrist et al. 2006). Intra-Golgi retrograde transport by COPI-GS28 vesicles has been assumed to maintain Golgi function by retrieving Golgi-resident proteins to younger cisternae in the progression of the entire Golgi stack from cis to trans, although direct evidence in vivo is lacking. We demonstrated that depletion of gosr-1 and ykt-6 strikingly reduced the amount of a Golgi-resident protein in the intestine [gosr-1(tm2800); ykt-6(RNAi),Fig. 5d,e]. These results clearly indicate that the intra-Golgi SNAREs, gosr-1 and ykt-6 are essential for the proper expression of Golgi-resident proteins, and suggest that gosr-1 functions in intra-Golgi retrograde transport cooperatively with ykt-6 in C. elegans intestinal cells.
During embryogenesis, knockdown of ykt-6 resulted in remarkably enhanced embryonic lethality in gosr-1 mutants [gosr-1(tm2800); ykt-6(RNAi),Fig. 3d,e], indicating that gosr-1 and ykt-6 also functions redundantly in the embryonic development. At this time, it is uncertain whether impairment of Golgi functions by reduced Golgi-resident proteins cause embryonic lethality in gosr-1(tm2800); ykt-6(RNAi) embryos. Multisubunit peripheral membrane protein complexes have recently been shown to play key roles in Golgi-associated membrane fusion events (Whyte & Munro 2002; Lupashin & Sztul 2005; Sztul & Lupashin 2006). One of these is the COG complex which appears to control the retention or retrieval of a subset of Golgi-localized proteins to intra-Golgi cisternae as a tether for COPI-mediated retrograde vesicles (Ram et al. 2002; Suvorova et al. 2002; Ungar et al. 2002; Oka et al. 2004; Shestakova et al. 2006; Vasile et al. 2006). Interestingly, we found that a mutation of COG3 [cogc-3(k181)] (Kubota & Nishiwaki 2006; Kubota et al. 2006), one of the COG proteins, also caused synergistic embryonic lethality in the gosr-1 mutant background (M. Maekawa, unpublished data). In addition, we found that weak inhibition of syntaxin-5 (F55A11.2), a t-SNARE required for intra-Golgi retrograde transport, caused severer embryonic lethality in gosr-1 mutants than in wild-type worms (99% Emb in gosr-1 mutants vs. 22% Emb in wild-type). These data suggest that impairment of intra-Golgi retrograde transport is embryonically lethal in C. elegans.
By using a conditional RNAi approach, we also demonstrated that depletion of both gosr-1 and ykt-6 [gosr-1(tm2800); ykt-6(RNAi)] reduced seam cell numbers (hermaphrodites, Fig. 4d) and caused missing ray phenotype (males, Fig. 3g,h) during post-embryonic development. As mentioned above, seam cells divide asymmetrically in a stem cell-like manner to give rise to extra epithelial cells and various neuronal cells including the sensory rays (Fig. S1b in Supporting Information). Therefore, both the reduced seam cell numbers and the missing ray phenotype observed in gosr-1(tm2800); ykt-6(RNAi) worms can be explained by defects in cell proliferation and/or differentiation of the seam cell lineage. Similar reduced seam cell numbers and a missing ray phenotype have been reported in mutants of rnt-1, a member of the RUNX family of transcriptional regulators (Kagoshima et al. 2007b). Several groups (Ji et al. 2004; Kagoshima et al. 2005, 2007a; Nimmo et al. 2005) have revealed that rnt-1 mutants showed defects in both cell proliferation and asymmetrical cell division (cell differentiation) in a seam cell lineage and concluded that these seam cell defects are responsible for reduced seam cell numbers and a missing ray phenotype observed in rnt-1 mutants. Other morphological defects in sensory rays, such as abnormal lumpy rays, swollen rays or fused rays have been reported in mutants of ram-5, mab-7 or mab-20 (semaphorin-2A) (Baird & Emmons 1990; Roy et al. 2000; Yu et al. 2000; Ikegami et al. 2004; Tsang et al. 2007). These mutations affect genes encoding transmembrane proteins (ram-5, mab-7) or secreted proteins (mab-20) that have been implicated in cell–cell communication in male tail development. We did not find morphological defects in gosr-1(tm2800); ykt-6(RNAi) worms similar to those observed in these mutants. Our data, together with these previous reports, suggest that gosr-1 and ykt-6 have an important role in cell proliferation and/or differentiation of stem cell-like seam cells in C. elegans.
In yeast and mammalian cells, GS28 and Ykt6 have been shown to form SNARE complexes and to function together in vesicular transport in the Golgi apparatus (McNew et al. 1997; Zhang & Hong 2001; Xu et al. 2002). Our results using gosr-1 mutants and ykt-6 RNAi clearly showed that, at least in C. elegans intestine, GOSR-1 and YKT-6 can compensate each other to maintain proper expression of a Golgi-localized protein (Fig. 5). This raises the possibility that in ykt-6 RNAi worms, GOSR-1 forms a complex with SNARE proteins other than YKT-6 and vice versa, and suggests that several combinations of the SNARE complex retain Golgi proteins in wild-type worms. Further biochemical analyses using gosr-1 mutants and ykt-6 RNAi worms should reveal the diversity of Golgi SNARE complexes involved in retrograde transport.
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Experimental procedures |
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Caenorhabditis elegans was maintained and genetically manipulated as described (Brenner 1974). The following mutations and integrated transgenes were used: gosr-1(tm2800)III, ykt-6(tm3575)III, him-5(e1490)V, wIs51[scm::gfp] and pwIs503[vha-6p::mans::gfp]. pwIs503 contains a signal sequence and a Golgi membrane-anchor domain of C. elegans alpha-mannosidase II (aman-2) fused to GFP (Rolls et al. 2002; Chen et al. 2006; Samuelson et al. 2007). gosr-1(tm2800) and ykt-6(tm3575) mutations were backcrossed at five times before further analysis. For analysis of male rays, we generated a male population using a him-5(e1490) mutant background.
Feeding RNAi
Feeding RNAi was performed as described previously (Kamath et al. 2001). In gosr-1(tm2800) enhancer screen, we selected 74 genes whose homologues are known to be involved in vesicular transport (Table S2 in Supporting Information). The corresponding bacterial RNAi feeding strains from the Ahringer library (Ashrafi et al. 2003) or from the ORFeome RNAi collection (Rual et al. 2004) were tested on wild-type and gosr-1(tm2800) mutants. L4 larvae of wild-type and gosr-1(tm2800) mutants were placed onto mock RNAi or onto ykt-6 RNAi feeding plates, incubated at 20 °C for 24 h, and transferred to fresh RNAi plates. The adult worms were allowed to lay eggs for 3 h and were scored for embryonic lethality 24 h after being laid. To examine effects of ykt-6 RNAi during post-embryonic development, L1 larvae of wild-type or gosr-1 mutants were mounted on the RNAi plates, and subsequently, we examined ray morphogenesis, scm::gfp-positive seam cells and intestinal expression of Golgi-localized mannosidase II::GFP at the young adult stage.
Preparation of transgenic worms
DNA injection into the C. elegans germ line was carried out as described previously (Mello et al. 1991). The array xhEx6001[gosr-1p::gfp] contains the plasmid pMM1 (gosr-1p::gfp) and pRF4 (rol-6(su1006)) for analysis of gosr-1 expression. pMM1 was generated by inserting a sequence containing the gosr-1 promoter region (a 2-kb region upstream of the gosr-1 initiation codon) into a pPD95.67 vector at the PstI and SalI sites. The primers used are gosr-1-F1, 5'-TTC GTC CTG CAG TTT TGA GAT GTA ACA ATC AA-3' and gosr-1-R1, 5'-CAA GTT TCG TCG ACC TTC TGT GTT CCT GAA AGT ATT-3'. For the rescue experiment, gosr-1 genomic region was amplified by PCR from the C. elegans genome with primers gosr-1-F2, 5'-TTC GTC CTG CAG TTT TGA GAT GTA ACA ATC AA-3' and gosr-1-R2, 5'-TTT GAA ACG TCG ACC TAT TGA TAA TCC AGA AAA TTG-3'. The PCR product was cloned into a pPD95.67 vector at the PstI and SalI sites [pMM2 (gosr-1::gfp)]. The array xhEx6004[gosr-1::gfp] contained the plasmid pMM2 and pHK1 (ges-1p::dsRed). The array xhEx6012[gosr-1p::gfp, ykt-6p::mCherry] contains the plasmid pMM1 and pMM3 (ykt-6p::mCherry). pMM3 was generated by inserting a sequence containing the ykt-6 promoter region (a 4-kb region upstream of the ykt-6 initiation codon) into a modified pPD95.67 vector, in which GFP is replaced with mCherry, at the SphI and NheI sites. The primers used are ykt-6-F, 5'-CGA TCC GCA TGC AAA ACT TTT TTT CCA ATC GC-3' and ykt-6-R, 5'-TTT CAT GCT AGC TGA AAA TTA TGA AAT TCA TG-3'.
Microscopy
Animals were mounted on a 5% agar pad on a glass slide and immobilized in 20 mM azide. Micrographs were taken on a Zeiss Axio Imager M1 or a Zeiss LSM 510 META confocal microscope.
Western blot analysis
Synchronized adult worms were collected and sonicated in SET buffer (10 mM Tris–HCl, pH 7.4, 1 mM EDTA and 250 mM sucrose) with protease inhibitors (5 µg/mL leupeptin, 5 µg/mL pepstatin A, 5 µg/mL aprotinin and 1 mM phenylmethylsulfonyl fluoride). After sonication, the lysates were centrifuged at 1000 x g for 10 min at 4 °C, and were subjected to SDS–PAGE and immunoblotting. The antibodies anti-GFP (JL8; Clontech, Palo Alto, CA, USA) and anti-actin (A3853; Sigma-Aldrich, Tokyo, Japan) were used at a dilution of 1 : 1000.
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Acknowledgements |
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Footnotes |
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* harai{at}mol.f.u-tokyo.ac.jp or takao{at}mol.f.u-tokyo.ac.jp |
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Received: 28 April 2009
Accepted: 14 May 2009
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