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The Homeodomain Iroquois Proteins Control Cell Cycle Progression and Regulate the Size of Developmental Fields.

Barrios N, González-Pérez E, Hernández R, Campuzano S - PLoS Genet. (2015)

Bottom Line: Here we show that in the imaginal discs, reduced function of Iroquois genes promotes cell proliferation by accelerating the G1 to S transition.Conversely, their increased expression causes cell-cycle arrest, down-regulating the activity of the Cyclin E/Cdk2 complex.Thus, Drosophila Iroquois proteins are able to regulate cell-autonomously the growth of the territories they specify.

View Article: PubMed Central - PubMed

Affiliation: Department of Development and Differentiation, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.

ABSTRACT
During development, proper differentiation and final organ size rely on the control of territorial specification and cell proliferation. Although many regulators of these processes have been identified, how both are coordinated remains largely unknown. The homeodomain Iroquois/Irx proteins play a key, evolutionarily conserved, role in territorial specification. Here we show that in the imaginal discs, reduced function of Iroquois genes promotes cell proliferation by accelerating the G1 to S transition. Conversely, their increased expression causes cell-cycle arrest, down-regulating the activity of the Cyclin E/Cdk2 complex. We demonstrate that physical interaction of the Iroquois protein Caupolican with Cyclin E-containing protein complexes, through its IRO box and Cyclin-binding domains, underlies its activity in cell-cycle control. Thus, Drosophila Iroquois proteins are able to regulate cell-autonomously the growth of the territories they specify. Moreover, our results provide a molecular mechanism for a role of Iroquois/Irx genes as tumour suppressors.

No MeSH data available.


Related in: MedlinePlus

The levels of Iro proteins modulate tumour-like growth.(A-C) Depletion of Iro proteins enhances eye growth in the sensitized background eyGal4>Dl>LacZ (note the enlarged and folded eyes in B, C, compare with A). Representative eyes are shown, along with the percentage of enlarged eyes for each genotype (average from two independent experiments, n>80 each). Flies were raised at 29°C. (D) Reduction of iro function (iroDFM3/+, or mirr depletion) enhances tumour-like growth in the >Dl >eyeful tumour model. (Left) Representative enlarged tumourous eye. (Right) Percentage of enlarged eyes in flies of the indicated genotypes (n>100, average value of three independent experiments). (E-I) Over-expression of caup reduces yki-induced overgrowth by CycE /Cdk2 inhibition. Compare the size of the sal domain (in green) in wing discs of the indicated genotypes. (G) Quantification of the area of the sal domain in third instar wing discs. Size domain was normalized to that of a sal>GFP>GFP>GFP wing discs (*p< 0.0001; **p<0.01). Discs are counterstained with Phalloidin (red).
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pgen.1005463.g007: The levels of Iro proteins modulate tumour-like growth.(A-C) Depletion of Iro proteins enhances eye growth in the sensitized background eyGal4>Dl>LacZ (note the enlarged and folded eyes in B, C, compare with A). Representative eyes are shown, along with the percentage of enlarged eyes for each genotype (average from two independent experiments, n>80 each). Flies were raised at 29°C. (D) Reduction of iro function (iroDFM3/+, or mirr depletion) enhances tumour-like growth in the >Dl >eyeful tumour model. (Left) Representative enlarged tumourous eye. (Right) Percentage of enlarged eyes in flies of the indicated genotypes (n>100, average value of three independent experiments). (E-I) Over-expression of caup reduces yki-induced overgrowth by CycE /Cdk2 inhibition. Compare the size of the sal domain (in green) in wing discs of the indicated genotypes. (G) Quantification of the area of the sal domain in third instar wing discs. Size domain was normalized to that of a sal>GFP>GFP>GFP wing discs (*p< 0.0001; **p<0.01). Discs are counterstained with Phalloidin (red).

Mentions: Over-expression of the Notch ligand Delta (Dl) causes the development of slightly enlarged eyes (eyGal4>Dl>lacZ flies, Fig 7A) and provides a sensitized genetic background useful to identify genes affecting cell proliferation and tumorigenesis [45]. We tested whether reduced activity of any of the Iro genes affected the size of eyGal4>Dl>lacZ eyes. Indeed, while partial depletion of Caup on its own had no discernible effect on eye size (S8B Fig), it increased both the size and the number of eyes that showed severe folding (Fig 7A and 7B). Similar enhancement of this mutant phenotype was obtained by co-expressing Dl and RNAi constructs targeted to ara or mirr (S8A, S8C and S8D Fig) or in combination with iroEGP7/+ (Fig 7C, 61% of the eyGal4>Dl>iroEGP7/+ eyes were enlarged compared with 39% of the eyes in eyGal4>Dl control flies).


The Homeodomain Iroquois Proteins Control Cell Cycle Progression and Regulate the Size of Developmental Fields.

Barrios N, González-Pérez E, Hernández R, Campuzano S - PLoS Genet. (2015)

The levels of Iro proteins modulate tumour-like growth.(A-C) Depletion of Iro proteins enhances eye growth in the sensitized background eyGal4>Dl>LacZ (note the enlarged and folded eyes in B, C, compare with A). Representative eyes are shown, along with the percentage of enlarged eyes for each genotype (average from two independent experiments, n>80 each). Flies were raised at 29°C. (D) Reduction of iro function (iroDFM3/+, or mirr depletion) enhances tumour-like growth in the >Dl >eyeful tumour model. (Left) Representative enlarged tumourous eye. (Right) Percentage of enlarged eyes in flies of the indicated genotypes (n>100, average value of three independent experiments). (E-I) Over-expression of caup reduces yki-induced overgrowth by CycE /Cdk2 inhibition. Compare the size of the sal domain (in green) in wing discs of the indicated genotypes. (G) Quantification of the area of the sal domain in third instar wing discs. Size domain was normalized to that of a sal>GFP>GFP>GFP wing discs (*p< 0.0001; **p<0.01). Discs are counterstained with Phalloidin (red).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4549242&req=5

pgen.1005463.g007: The levels of Iro proteins modulate tumour-like growth.(A-C) Depletion of Iro proteins enhances eye growth in the sensitized background eyGal4>Dl>LacZ (note the enlarged and folded eyes in B, C, compare with A). Representative eyes are shown, along with the percentage of enlarged eyes for each genotype (average from two independent experiments, n>80 each). Flies were raised at 29°C. (D) Reduction of iro function (iroDFM3/+, or mirr depletion) enhances tumour-like growth in the >Dl >eyeful tumour model. (Left) Representative enlarged tumourous eye. (Right) Percentage of enlarged eyes in flies of the indicated genotypes (n>100, average value of three independent experiments). (E-I) Over-expression of caup reduces yki-induced overgrowth by CycE /Cdk2 inhibition. Compare the size of the sal domain (in green) in wing discs of the indicated genotypes. (G) Quantification of the area of the sal domain in third instar wing discs. Size domain was normalized to that of a sal>GFP>GFP>GFP wing discs (*p< 0.0001; **p<0.01). Discs are counterstained with Phalloidin (red).
Mentions: Over-expression of the Notch ligand Delta (Dl) causes the development of slightly enlarged eyes (eyGal4>Dl>lacZ flies, Fig 7A) and provides a sensitized genetic background useful to identify genes affecting cell proliferation and tumorigenesis [45]. We tested whether reduced activity of any of the Iro genes affected the size of eyGal4>Dl>lacZ eyes. Indeed, while partial depletion of Caup on its own had no discernible effect on eye size (S8B Fig), it increased both the size and the number of eyes that showed severe folding (Fig 7A and 7B). Similar enhancement of this mutant phenotype was obtained by co-expressing Dl and RNAi constructs targeted to ara or mirr (S8A, S8C and S8D Fig) or in combination with iroEGP7/+ (Fig 7C, 61% of the eyGal4>Dl>iroEGP7/+ eyes were enlarged compared with 39% of the eyes in eyGal4>Dl control flies).

Bottom Line: Here we show that in the imaginal discs, reduced function of Iroquois genes promotes cell proliferation by accelerating the G1 to S transition.Conversely, their increased expression causes cell-cycle arrest, down-regulating the activity of the Cyclin E/Cdk2 complex.Thus, Drosophila Iroquois proteins are able to regulate cell-autonomously the growth of the territories they specify.

View Article: PubMed Central - PubMed

Affiliation: Department of Development and Differentiation, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.

ABSTRACT
During development, proper differentiation and final organ size rely on the control of territorial specification and cell proliferation. Although many regulators of these processes have been identified, how both are coordinated remains largely unknown. The homeodomain Iroquois/Irx proteins play a key, evolutionarily conserved, role in territorial specification. Here we show that in the imaginal discs, reduced function of Iroquois genes promotes cell proliferation by accelerating the G1 to S transition. Conversely, their increased expression causes cell-cycle arrest, down-regulating the activity of the Cyclin E/Cdk2 complex. We demonstrate that physical interaction of the Iroquois protein Caupolican with Cyclin E-containing protein complexes, through its IRO box and Cyclin-binding domains, underlies its activity in cell-cycle control. Thus, Drosophila Iroquois proteins are able to regulate cell-autonomously the growth of the territories they specify. Moreover, our results provide a molecular mechanism for a role of Iroquois/Irx genes as tumour suppressors.

No MeSH data available.


Related in: MedlinePlus