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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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ces-1(n703gf); cya-1(bc416) affects the division of the NSM neuroblast.(A) The presence of NSMs, undead NSM sister cells, and non-dividing NSM neuroblasts was analyzed in L3, L4 larvae using the reporter Ptph-1his-24::gfp (bcIs66). All strains analyzed were homozygous for bcIs66. Epifluorescence images overlaid with DIC. (B) The NSM neuroblast division was analyzed in embryos using the reporter Ppie-1mCherry::phPLC1δ (ltIs44) or Ppie-1gfp::phPLC1δ (ltIs38). Epifluorescence images were taken before (‘comma’) and after the NSM neuroblast division (‘1.5-fold’). In the case of ces-1(n703gf); cya-1(bc416), the NSM neuroblasts had not divided at the time the analysis had to be terminated due to the beginning of muscle twitching (around the 2-fold stage). White arrows point to the NSM neuroblasts, blue and orange arrows point to the NSMs and NSM sister cells, respectively. All strains analyzed were homozygous for ltIs44 and bcIs66, except ces-1(n703gf), which was homozygous for ltIs38 and bcIs66. (C) Quantification of the percentage of NSM neuroblasts dividing in wild-type, ces-1(n703gf), ces-1(n703gf); cya-1(bc416), cya-1(bc416) and cdc-25.2(RNAi) embryos. cdc-25.2(RNAi) was performed by injection. n indicates the number of NSM neuroblasts analyzed.
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pgen-1003884-g001: ces-1(n703gf); cya-1(bc416) affects the division of the NSM neuroblast.(A) The presence of NSMs, undead NSM sister cells, and non-dividing NSM neuroblasts was analyzed in L3, L4 larvae using the reporter Ptph-1his-24::gfp (bcIs66). All strains analyzed were homozygous for bcIs66. Epifluorescence images overlaid with DIC. (B) The NSM neuroblast division was analyzed in embryos using the reporter Ppie-1mCherry::phPLC1δ (ltIs44) or Ppie-1gfp::phPLC1δ (ltIs38). Epifluorescence images were taken before (‘comma’) and after the NSM neuroblast division (‘1.5-fold’). In the case of ces-1(n703gf); cya-1(bc416), the NSM neuroblasts had not divided at the time the analysis had to be terminated due to the beginning of muscle twitching (around the 2-fold stage). White arrows point to the NSM neuroblasts, blue and orange arrows point to the NSMs and NSM sister cells, respectively. All strains analyzed were homozygous for ltIs44 and bcIs66, except ces-1(n703gf), which was homozygous for ltIs38 and bcIs66. (C) Quantification of the percentage of NSM neuroblasts dividing in wild-type, ces-1(n703gf), ces-1(n703gf); cya-1(bc416), cya-1(bc416) and cdc-25.2(RNAi) embryos. cdc-25.2(RNAi) was performed by injection. n indicates the number of NSM neuroblasts analyzed.

Mentions: Wild-type larvae carrying the Ptph-1his-24::gfp reporter (tph, tryptophane hydroxylase; his, histone structural gene), which is specifically expressed in serotonergic neurons (and labels the nuclei of these neurons) [24], have two GFP-positive neurons in the anterior pharynx, the left and right NSM (Figure 1A, +/+). In animals carrying a gf mutation of ces-1, n703, the NSM neuroblast divides symmetrically, resulting in two daughter cells of similar sizes, both of which survive [17], [19]. Therefore, ces-1(n703gf) larvae carrying the Ptph-1his-24::gfp reporter have four GFP-positive neurons in the head region, the left and right NSM and the left and right ‘undead’ NSM sister cell (Figure 1A, ces-1(n703gf)). To identify targets of the CES-1 protein involved in the asymmetric division of the NSM neuroblast, we performed a ces-1(n703gf) suppressor screen using the Ptph-1his-24::gfp reporter as a tool. Specifically, we screened mutagenized ces-1(n703gf) animals for mutations that cause a reduction in the number of GFP-positive NSMs and undead NSM sister cells (i.e. less than four GFP-positive cells in the anterior pharynx). Using this approach, we isolated the mutation bc416. At 15°C, 100% of ces-1(n703gf) larvae have four GFP-positive cells. In contrast, only 5% of ces-1(n703gf) larvae homozygous for bc416 (ces-1(n703gf); bc416) have four GFP-positive cells (Table 1). The bc416 mutation is recessive and does not show maternal rescue (data not shown; Table S1).


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) affects the division of the NSM neuroblast.(A) The presence of NSMs, undead NSM sister cells, and non-dividing NSM neuroblasts was analyzed in L3, L4 larvae using the reporter Ptph-1his-24::gfp (bcIs66). All strains analyzed were homozygous for bcIs66. Epifluorescence images overlaid with DIC. (B) The NSM neuroblast division was analyzed in embryos using the reporter Ppie-1mCherry::phPLC1δ (ltIs44) or Ppie-1gfp::phPLC1δ (ltIs38). Epifluorescence images were taken before (‘comma’) and after the NSM neuroblast division (‘1.5-fold’). In the case of ces-1(n703gf); cya-1(bc416), the NSM neuroblasts had not divided at the time the analysis had to be terminated due to the beginning of muscle twitching (around the 2-fold stage). White arrows point to the NSM neuroblasts, blue and orange arrows point to the NSMs and NSM sister cells, respectively. All strains analyzed were homozygous for ltIs44 and bcIs66, except ces-1(n703gf), which was homozygous for ltIs38 and bcIs66. (C) Quantification of the percentage of NSM neuroblasts dividing in wild-type, ces-1(n703gf), ces-1(n703gf); cya-1(bc416), cya-1(bc416) and cdc-25.2(RNAi) embryos. cdc-25.2(RNAi) was performed by injection. n indicates the number of NSM neuroblasts analyzed.
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Related In: Results  -  Collection

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pgen-1003884-g001: ces-1(n703gf); cya-1(bc416) affects the division of the NSM neuroblast.(A) The presence of NSMs, undead NSM sister cells, and non-dividing NSM neuroblasts was analyzed in L3, L4 larvae using the reporter Ptph-1his-24::gfp (bcIs66). All strains analyzed were homozygous for bcIs66. Epifluorescence images overlaid with DIC. (B) The NSM neuroblast division was analyzed in embryos using the reporter Ppie-1mCherry::phPLC1δ (ltIs44) or Ppie-1gfp::phPLC1δ (ltIs38). Epifluorescence images were taken before (‘comma’) and after the NSM neuroblast division (‘1.5-fold’). In the case of ces-1(n703gf); cya-1(bc416), the NSM neuroblasts had not divided at the time the analysis had to be terminated due to the beginning of muscle twitching (around the 2-fold stage). White arrows point to the NSM neuroblasts, blue and orange arrows point to the NSMs and NSM sister cells, respectively. All strains analyzed were homozygous for ltIs44 and bcIs66, except ces-1(n703gf), which was homozygous for ltIs38 and bcIs66. (C) Quantification of the percentage of NSM neuroblasts dividing in wild-type, ces-1(n703gf), ces-1(n703gf); cya-1(bc416), cya-1(bc416) and cdc-25.2(RNAi) embryos. cdc-25.2(RNAi) was performed by injection. n indicates the number of NSM neuroblasts analyzed.
Mentions: Wild-type larvae carrying the Ptph-1his-24::gfp reporter (tph, tryptophane hydroxylase; his, histone structural gene), which is specifically expressed in serotonergic neurons (and labels the nuclei of these neurons) [24], have two GFP-positive neurons in the anterior pharynx, the left and right NSM (Figure 1A, +/+). In animals carrying a gf mutation of ces-1, n703, the NSM neuroblast divides symmetrically, resulting in two daughter cells of similar sizes, both of which survive [17], [19]. Therefore, ces-1(n703gf) larvae carrying the Ptph-1his-24::gfp reporter have four GFP-positive neurons in the head region, the left and right NSM and the left and right ‘undead’ NSM sister cell (Figure 1A, ces-1(n703gf)). To identify targets of the CES-1 protein involved in the asymmetric division of the NSM neuroblast, we performed a ces-1(n703gf) suppressor screen using the Ptph-1his-24::gfp reporter as a tool. Specifically, we screened mutagenized ces-1(n703gf) animals for mutations that cause a reduction in the number of GFP-positive NSMs and undead NSM sister cells (i.e. less than four GFP-positive cells in the anterior pharynx). Using this approach, we isolated the mutation bc416. At 15°C, 100% of ces-1(n703gf) larvae have four GFP-positive cells. In contrast, only 5% of ces-1(n703gf) larvae homozygous for bc416 (ces-1(n703gf); bc416) have four GFP-positive cells (Table 1). The bc416 mutation is recessive and does not show maternal rescue (data not shown; Table S1).

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