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C. elegans FOG-3/Tob can either promote or inhibit germline proliferation, depending on gene dosage and genetic context.

Snow JJ, Lee MH, Verheyden J, Kroll-Conner PL, Kimble J - Oncogene (2012)

Bottom Line: Thus, fog-3 mutants possess fewer germ cells than normal, a modest but reproducible decrease observed for each of two distinct fog-3 alleles.Finally, we show that FOG-3 and FBF work together to promote tumor formation in animals carrying oncogenic Notch mutations.A similar effect was not observed when germline tumors were induced by manipulation of other regulators; therefore, this FOG-3 tumor-promoting effect is context dependent.

View Article: PubMed Central - PubMed

Affiliation: Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI, USA.

ABSTRACT
Vertebrate Tob/BTG proteins inhibit cell proliferation when overexpressed in tissue-culture cells, and they can function as tumor suppressors in mice. The single Caenorhabditis elegans Tob/BTG ortholog, FOG-3, by contrast, was identified from its loss-of-function phenotype as a regulator of sperm fate specification. Here we report that FOG-3 also regulates proliferation in the germline tissue. We first demonstrate that FOG-3 is a positive regulator of germline proliferation. Thus, fog-3 mutants possess fewer germ cells than normal, a modest but reproducible decrease observed for each of two distinct fog-3 alleles. A similar decrease also occurred in fog-3/+ heterozygotes, again for both fog-3 alleles, revealing a haplo-insufficient effect on proliferation. Therefore, FOG-3 normally promotes proliferation, and two copies of the fog-3 gene are required for this function. We next overexpressed FOG-3 by removal of FBF, the collective term for FBF-1 and FBF-2, two nearly identical PUF RNA-binding proteins. We find that overexpressed FOG-3 blocks proliferation in fbf-1 fbf-2 mutants; whereas germ cells stop dividing and instead differentiate in fbf-1 fbf-2 double mutants, they continue to proliferate in fog-3; fbf-1 fbf-2 triple mutants. Therefore, like its vertebrate Tob/BTG cousins, overexpressed FOG-3 is 'antiproliferative'. Indeed, some fog-3; fbf-1 fbf-2 mutants possess small tumors, suggesting that FOG-3 can act as a tumor suppressor. Finally, we show that FOG-3 and FBF work together to promote tumor formation in animals carrying oncogenic Notch mutations. A similar effect was not observed when germline tumors were induced by manipulation of other regulators; therefore, this FOG-3 tumor-promoting effect is context dependent. We conclude that FOG-3 can either promote or inhibit proliferation in a manner that is sensitive to both genetic context and gene dosage. The discovery of these FOG-3 effects on proliferation has implications for our understanding of vertebrate Tob/BTG proteins and their influence on normal development and tumorigenesis.

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FOG-3 promotes robust germline proliferation. (a) FOG-3 is a member of the Tob/BTG protein family. The family signature is the BTG domain (blue), which contains two highly conserved regions, Box A and Box B (39). The C-terminal amino acid sequence is not conserved except for the PAM2 motif among vertebrate Tob proteins (40) and the TF motif among vertebrate and C. elegans proteins (16). (b) Average number of germ cells per gonadal arm in mid-L4 larvae of genotypes as designated. Bal, balancer chromosome used to maintain heterozygotes. The p-values are given for comparisons of germ cell counts marked by brackets; these p-values were generated using a Mann-Whitney test; similar numbers were also obtained using a two-tailed t-test. CI, confidence interval in number of germ cells from average. n, number of gonadal arms counted for each genotype.
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Figure 1: FOG-3 promotes robust germline proliferation. (a) FOG-3 is a member of the Tob/BTG protein family. The family signature is the BTG domain (blue), which contains two highly conserved regions, Box A and Box B (39). The C-terminal amino acid sequence is not conserved except for the PAM2 motif among vertebrate Tob proteins (40) and the TF motif among vertebrate and C. elegans proteins (16). (b) Average number of germ cells per gonadal arm in mid-L4 larvae of genotypes as designated. Bal, balancer chromosome used to maintain heterozygotes. The p-values are given for comparisons of germ cell counts marked by brackets; these p-values were generated using a Mann-Whitney test; similar numbers were also obtained using a two-tailed t-test. CI, confidence interval in number of germ cells from average. n, number of gonadal arms counted for each genotype.

Mentions: Analysis of Tob/BTG proteins in vertebrate organisms has been constrained by the complexity of vertebrate tissues and the existence of multiple homologs (e.g. Tob1, Tob2, BTG1, BTG2, BTG3 and BTG4 in humans). Here we take advantage of the genetic power and relative simplicity of the nematode Caenorhabditis elegans to investigate the role of its single Tob/BTG ortholog in the regulation of proliferation. This ortholog (Figure 1a) was identified originally for its role in sperm fate specification and named FOG-3 for its mutant phenotype (feminization of the germline) (15, 16). The only defect observed in fog-3 mutants was sexual transformation of the germline; in the absence of FOG-3, germ cells that normally differentiate as sperm instead become oocytes. Most importantly, no conspicuous defect in proliferation was observed in fog-3 mutants.


C. elegans FOG-3/Tob can either promote or inhibit germline proliferation, depending on gene dosage and genetic context.

Snow JJ, Lee MH, Verheyden J, Kroll-Conner PL, Kimble J - Oncogene (2012)

FOG-3 promotes robust germline proliferation. (a) FOG-3 is a member of the Tob/BTG protein family. The family signature is the BTG domain (blue), which contains two highly conserved regions, Box A and Box B (39). The C-terminal amino acid sequence is not conserved except for the PAM2 motif among vertebrate Tob proteins (40) and the TF motif among vertebrate and C. elegans proteins (16). (b) Average number of germ cells per gonadal arm in mid-L4 larvae of genotypes as designated. Bal, balancer chromosome used to maintain heterozygotes. The p-values are given for comparisons of germ cell counts marked by brackets; these p-values were generated using a Mann-Whitney test; similar numbers were also obtained using a two-tailed t-test. CI, confidence interval in number of germ cells from average. n, number of gonadal arms counted for each genotype.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3475796&req=5

Figure 1: FOG-3 promotes robust germline proliferation. (a) FOG-3 is a member of the Tob/BTG protein family. The family signature is the BTG domain (blue), which contains two highly conserved regions, Box A and Box B (39). The C-terminal amino acid sequence is not conserved except for the PAM2 motif among vertebrate Tob proteins (40) and the TF motif among vertebrate and C. elegans proteins (16). (b) Average number of germ cells per gonadal arm in mid-L4 larvae of genotypes as designated. Bal, balancer chromosome used to maintain heterozygotes. The p-values are given for comparisons of germ cell counts marked by brackets; these p-values were generated using a Mann-Whitney test; similar numbers were also obtained using a two-tailed t-test. CI, confidence interval in number of germ cells from average. n, number of gonadal arms counted for each genotype.
Mentions: Analysis of Tob/BTG proteins in vertebrate organisms has been constrained by the complexity of vertebrate tissues and the existence of multiple homologs (e.g. Tob1, Tob2, BTG1, BTG2, BTG3 and BTG4 in humans). Here we take advantage of the genetic power and relative simplicity of the nematode Caenorhabditis elegans to investigate the role of its single Tob/BTG ortholog in the regulation of proliferation. This ortholog (Figure 1a) was identified originally for its role in sperm fate specification and named FOG-3 for its mutant phenotype (feminization of the germline) (15, 16). The only defect observed in fog-3 mutants was sexual transformation of the germline; in the absence of FOG-3, germ cells that normally differentiate as sperm instead become oocytes. Most importantly, no conspicuous defect in proliferation was observed in fog-3 mutants.

Bottom Line: Thus, fog-3 mutants possess fewer germ cells than normal, a modest but reproducible decrease observed for each of two distinct fog-3 alleles.Finally, we show that FOG-3 and FBF work together to promote tumor formation in animals carrying oncogenic Notch mutations.A similar effect was not observed when germline tumors were induced by manipulation of other regulators; therefore, this FOG-3 tumor-promoting effect is context dependent.

View Article: PubMed Central - PubMed

Affiliation: Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI, USA.

ABSTRACT
Vertebrate Tob/BTG proteins inhibit cell proliferation when overexpressed in tissue-culture cells, and they can function as tumor suppressors in mice. The single Caenorhabditis elegans Tob/BTG ortholog, FOG-3, by contrast, was identified from its loss-of-function phenotype as a regulator of sperm fate specification. Here we report that FOG-3 also regulates proliferation in the germline tissue. We first demonstrate that FOG-3 is a positive regulator of germline proliferation. Thus, fog-3 mutants possess fewer germ cells than normal, a modest but reproducible decrease observed for each of two distinct fog-3 alleles. A similar decrease also occurred in fog-3/+ heterozygotes, again for both fog-3 alleles, revealing a haplo-insufficient effect on proliferation. Therefore, FOG-3 normally promotes proliferation, and two copies of the fog-3 gene are required for this function. We next overexpressed FOG-3 by removal of FBF, the collective term for FBF-1 and FBF-2, two nearly identical PUF RNA-binding proteins. We find that overexpressed FOG-3 blocks proliferation in fbf-1 fbf-2 mutants; whereas germ cells stop dividing and instead differentiate in fbf-1 fbf-2 double mutants, they continue to proliferate in fog-3; fbf-1 fbf-2 triple mutants. Therefore, like its vertebrate Tob/BTG cousins, overexpressed FOG-3 is 'antiproliferative'. Indeed, some fog-3; fbf-1 fbf-2 mutants possess small tumors, suggesting that FOG-3 can act as a tumor suppressor. Finally, we show that FOG-3 and FBF work together to promote tumor formation in animals carrying oncogenic Notch mutations. A similar effect was not observed when germline tumors were induced by manipulation of other regulators; therefore, this FOG-3 tumor-promoting effect is context dependent. We conclude that FOG-3 can either promote or inhibit proliferation in a manner that is sensitive to both genetic context and gene dosage. The discovery of these FOG-3 effects on proliferation has implications for our understanding of vertebrate Tob/BTG proteins and their influence on normal development and tumorigenesis.

Show MeSH
Related in: MedlinePlus