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Coordination of cell proliferation and cell fate determination by CES-1 snail.

Yan B, Memar N, Gallinger J, Conradt B - PLoS Genet. (2013)

Bottom Line: We now demonstrate that CES-1 also affects cell cycle progression in this lineage.Finally, we provide evidence that dnj-11 MIDA1 not only regulate CES-1 activity in the context of cell polarity and apoptosis but also in the context of cell cycle progression.In mammals, the over-expression of Snail-related genes has been implicated in tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Center for Integrated Protein Science, Department of Biology II, Ludwig-Maximilians-University, Munich, Planegg-Martinsried, Germany ; Department of Genetics, MCB Graduate Program, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.

ABSTRACT
The coordination of cell proliferation and cell fate determination is critical during development but the mechanisms through which this is accomplished are unclear. We present evidence that the Snail-related transcription factor CES-1 of Caenorhabditis elegans coordinates these processes in a specific cell lineage. CES-1 can cause loss of cell polarity in the NSM neuroblast. By repressing the transcription of the BH3-only gene egl-1, CES-1 can also suppress apoptosis in the daughters of the NSM neuroblasts. We now demonstrate that CES-1 also affects cell cycle progression in this lineage. Specifically, we found that CES-1 can repress the transcription of the cdc-25.2 gene, which encodes a Cdc25-like phosphatase, thereby enhancing the block in NSM neuroblast division caused by the partial loss of cya-1, which encodes Cyclin A. Our results indicate that CDC-25.2 and CYA-1 control specific cell divisions and that the over-expression of the ces-1 gene leads to incorrect regulation of this functional 'module'. Finally, we provide evidence that dnj-11 MIDA1 not only regulate CES-1 activity in the context of cell polarity and apoptosis but also in the context of cell cycle progression. In mammals, the over-expression of Snail-related genes has been implicated in tumorigenesis. Our findings support the notion that the oncogenic potential of Snail-related transcription factors lies in their capability to, simultaneously, affect cell cycle progression, cell polarity and apoptosis and, hence, the coordination of cell proliferation and cell fate determination.

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Related in: MedlinePlus

ces-1(n703gf); cya-1(bc416) blocks cell divisions in the ABarp, C and E lineages.All strains analyzed were homozygous for bcIs66. Lineage analyses were performed for two (wild-type, +/+), three (ces-1(n703gf); cya-1(bc416)) and three (cdc-25.2(RNAi)) embryos raised at 25°C. The ABarp, C and E lineages are shown. Vertical axis indicates approximate time in min after the 1st round of embryonic division, in which P0 divides into AB and P1. In the case of ces-1(n703gf); cya-1(bc416), cell division defects observed in three out of three embryos are depicted in red, defects found in two out of three embryos are depicted in blue, and defects found in one out of three embryos are depicted in orange. In the case of cdc-25.2(RNAi), RNAi was carried out by injection. Since there is some variability of the RNAi effect, the lineage shown here was derived from the embryo with the strongest phenotype (cell division defects observed in this embryo are depicted in green), and the lineages from the other two cdc-25.2(RNAi) embryos are shown in Figure S6. The severe cell division defects in the ABarp, C and E lineages were seen in all three cdc-25.2(RNAi) embryos. The cell death in the ABarp lineage is labeled with the cross. The defects in the C lineage and ABarp lineage result in a defect in the formation of the hypodermis (the mitoses that generate hyp7, hyp5, hyp11, H0, H1, H2, V1, V2, V4, and V6 fail to occur).
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pgen-1003884-g003: ces-1(n703gf); cya-1(bc416) blocks cell divisions in the ABarp, C and E lineages.All strains analyzed were homozygous for bcIs66. Lineage analyses were performed for two (wild-type, +/+), three (ces-1(n703gf); cya-1(bc416)) and three (cdc-25.2(RNAi)) embryos raised at 25°C. The ABarp, C and E lineages are shown. Vertical axis indicates approximate time in min after the 1st round of embryonic division, in which P0 divides into AB and P1. In the case of ces-1(n703gf); cya-1(bc416), cell division defects observed in three out of three embryos are depicted in red, defects found in two out of three embryos are depicted in blue, and defects found in one out of three embryos are depicted in orange. In the case of cdc-25.2(RNAi), RNAi was carried out by injection. Since there is some variability of the RNAi effect, the lineage shown here was derived from the embryo with the strongest phenotype (cell division defects observed in this embryo are depicted in green), and the lineages from the other two cdc-25.2(RNAi) embryos are shown in Figure S6. The severe cell division defects in the ABarp, C and E lineages were seen in all three cdc-25.2(RNAi) embryos. The cell death in the ABarp lineage is labeled with the cross. The defects in the C lineage and ABarp lineage result in a defect in the formation of the hypodermis (the mitoses that generate hyp7, hyp5, hyp11, H0, H1, H2, V1, V2, V4, and V6 fail to occur).

Mentions: Since a highly penetrant Emb phenotype was observed in ces-1(n703gf); bc416 animals raised at 25°C, we investigated whether cell divisions other than the divisions of the NSM neuroblasts are affected in these animals. A systematic analysis of all cell lineages using 4D lineage analysis [29] showed that cell division defects are not restricted to the NSM lineage. We found that at 25°C, the ABarp, C and E lineages are also affected in ces-1(n703gf); bc416 animals (Figure 3). All other lineages were not affected. ABarp is a major hypodermal precursor and the C founder cell generates additional posterior and dorsal hypodermal cells [18]. In the ABarp lineage, most cell divisions that give rise to ventrolateral ectoblasts (V1 to V6) are blocked (Figure 3). Furthermore, in the C lineage, many cell divisions that generate the embryonic large hypodermal syncytium (hyp7) fail to occur (Figure 3). The defects in the ABarp and C lineage most likely cause or contribute to the observed hypodermal abnormalities (Figure 2B, C). A failure in the formation of the hypodermis has previously been shown to cause embryonic lethality [30]. In addition, the phenotype of arrested ces-1(n703gf); bc416 embryos is similar to the phenotype of mutants with hypodermal defects [30]. Therefore, the cell division defects in the ABarp and C lineages observed in ces-1(n703gf); bc416 animals most probably cause the Emb phenotype exhibited by these animals. In addition, we identified variable defects in the E lineage. Specifically, some cell divisions of the 7th round of division during C. elegans embryogenesis do not occur in the E lineage (Figure 3). Based on these observations, we conclude that in the ces-1(n703gf) background and at 25°C, bc416 affects the divisions of cells other than the NSM neuroblasts. (The defects caused by bc416 in an otherwise wild-type background will be discussed below.)


Coordination of cell proliferation and cell fate determination by CES-1 snail.

Yan B, Memar N, Gallinger J, Conradt B - PLoS Genet. (2013)

ces-1(n703gf); cya-1(bc416) blocks cell divisions in the ABarp, C and E lineages.All strains analyzed were homozygous for bcIs66. Lineage analyses were performed for two (wild-type, +/+), three (ces-1(n703gf); cya-1(bc416)) and three (cdc-25.2(RNAi)) embryos raised at 25°C. The ABarp, C and E lineages are shown. Vertical axis indicates approximate time in min after the 1st round of embryonic division, in which P0 divides into AB and P1. In the case of ces-1(n703gf); cya-1(bc416), cell division defects observed in three out of three embryos are depicted in red, defects found in two out of three embryos are depicted in blue, and defects found in one out of three embryos are depicted in orange. In the case of cdc-25.2(RNAi), RNAi was carried out by injection. Since there is some variability of the RNAi effect, the lineage shown here was derived from the embryo with the strongest phenotype (cell division defects observed in this embryo are depicted in green), and the lineages from the other two cdc-25.2(RNAi) embryos are shown in Figure S6. The severe cell division defects in the ABarp, C and E lineages were seen in all three cdc-25.2(RNAi) embryos. The cell death in the ABarp lineage is labeled with the cross. The defects in the C lineage and ABarp lineage result in a defect in the formation of the hypodermis (the mitoses that generate hyp7, hyp5, hyp11, H0, H1, H2, V1, V2, V4, and V6 fail to occur).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3814331&req=5

pgen-1003884-g003: ces-1(n703gf); cya-1(bc416) blocks cell divisions in the ABarp, C and E lineages.All strains analyzed were homozygous for bcIs66. Lineage analyses were performed for two (wild-type, +/+), three (ces-1(n703gf); cya-1(bc416)) and three (cdc-25.2(RNAi)) embryos raised at 25°C. The ABarp, C and E lineages are shown. Vertical axis indicates approximate time in min after the 1st round of embryonic division, in which P0 divides into AB and P1. In the case of ces-1(n703gf); cya-1(bc416), cell division defects observed in three out of three embryos are depicted in red, defects found in two out of three embryos are depicted in blue, and defects found in one out of three embryos are depicted in orange. In the case of cdc-25.2(RNAi), RNAi was carried out by injection. Since there is some variability of the RNAi effect, the lineage shown here was derived from the embryo with the strongest phenotype (cell division defects observed in this embryo are depicted in green), and the lineages from the other two cdc-25.2(RNAi) embryos are shown in Figure S6. The severe cell division defects in the ABarp, C and E lineages were seen in all three cdc-25.2(RNAi) embryos. The cell death in the ABarp lineage is labeled with the cross. The defects in the C lineage and ABarp lineage result in a defect in the formation of the hypodermis (the mitoses that generate hyp7, hyp5, hyp11, H0, H1, H2, V1, V2, V4, and V6 fail to occur).
Mentions: Since a highly penetrant Emb phenotype was observed in ces-1(n703gf); bc416 animals raised at 25°C, we investigated whether cell divisions other than the divisions of the NSM neuroblasts are affected in these animals. A systematic analysis of all cell lineages using 4D lineage analysis [29] showed that cell division defects are not restricted to the NSM lineage. We found that at 25°C, the ABarp, C and E lineages are also affected in ces-1(n703gf); bc416 animals (Figure 3). All other lineages were not affected. ABarp is a major hypodermal precursor and the C founder cell generates additional posterior and dorsal hypodermal cells [18]. In the ABarp lineage, most cell divisions that give rise to ventrolateral ectoblasts (V1 to V6) are blocked (Figure 3). Furthermore, in the C lineage, many cell divisions that generate the embryonic large hypodermal syncytium (hyp7) fail to occur (Figure 3). The defects in the ABarp and C lineage most likely cause or contribute to the observed hypodermal abnormalities (Figure 2B, C). A failure in the formation of the hypodermis has previously been shown to cause embryonic lethality [30]. In addition, the phenotype of arrested ces-1(n703gf); bc416 embryos is similar to the phenotype of mutants with hypodermal defects [30]. Therefore, the cell division defects in the ABarp and C lineages observed in ces-1(n703gf); bc416 animals most probably cause the Emb phenotype exhibited by these animals. In addition, we identified variable defects in the E lineage. Specifically, some cell divisions of the 7th round of division during C. elegans embryogenesis do not occur in the E lineage (Figure 3). Based on these observations, we conclude that in the ces-1(n703gf) background and at 25°C, bc416 affects the divisions of cells other than the NSM neuroblasts. (The defects caused by bc416 in an otherwise wild-type background will be discussed below.)

Bottom Line: We now demonstrate that CES-1 also affects cell cycle progression in this lineage.Finally, we provide evidence that dnj-11 MIDA1 not only regulate CES-1 activity in the context of cell polarity and apoptosis but also in the context of cell cycle progression.In mammals, the over-expression of Snail-related genes has been implicated in tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Center for Integrated Protein Science, Department of Biology II, Ludwig-Maximilians-University, Munich, Planegg-Martinsried, Germany ; Department of Genetics, MCB Graduate Program, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.

ABSTRACT
The coordination of cell proliferation and cell fate determination is critical during development but the mechanisms through which this is accomplished are unclear. We present evidence that the Snail-related transcription factor CES-1 of Caenorhabditis elegans coordinates these processes in a specific cell lineage. CES-1 can cause loss of cell polarity in the NSM neuroblast. By repressing the transcription of the BH3-only gene egl-1, CES-1 can also suppress apoptosis in the daughters of the NSM neuroblasts. We now demonstrate that CES-1 also affects cell cycle progression in this lineage. Specifically, we found that CES-1 can repress the transcription of the cdc-25.2 gene, which encodes a Cdc25-like phosphatase, thereby enhancing the block in NSM neuroblast division caused by the partial loss of cya-1, which encodes Cyclin A. Our results indicate that CDC-25.2 and CYA-1 control specific cell divisions and that the over-expression of the ces-1 gene leads to incorrect regulation of this functional 'module'. Finally, we provide evidence that dnj-11 MIDA1 not only regulate CES-1 activity in the context of cell polarity and apoptosis but also in the context of cell cycle progression. In mammals, the over-expression of Snail-related genes has been implicated in tumorigenesis. Our findings support the notion that the oncogenic potential of Snail-related transcription factors lies in their capability to, simultaneously, affect cell cycle progression, cell polarity and apoptosis and, hence, the coordination of cell proliferation and cell fate determination.

Show MeSH
Related in: MedlinePlus