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Dally Proteoglycan Mediates the Autonomous and Nonautonomous Effects on Tissue Growth Caused by Activation of the PI3K and TOR Pathways.

Ferreira A, Milán M - PLoS Biol. (2015)

Bottom Line: Activation of these pathways leads to an autonomous induction of tissue overgrowth and to a remarkable nonautonomous reduction in growth and proliferation rates of adjacent cell populations.The observed autonomous and nonautonomous effects on tissue growth rely on the up-regulation of the proteoglycan Dally, a major element involved in modulating the spreading, stability, and activity of the growth promoting Decapentaplegic (Dpp)/transforming growth factor β(TGF-β) signaling molecule.Our findings indicate that a reduction in the amount of available growth factors contributes to the outcompetition of wild-type cells by overgrowing cell populations.

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.

ABSTRACT
How cells acquiring mutations in tumor suppressor genes outcompete neighboring wild-type cells is poorly understood. The phosphatidylinositol 3-kinase (PI3K)-phosphatase with tensin homology (PTEN) and tuberous sclerosis complex (TSC)-target of rapamycin (TOR) pathways are frequently activated in human cancer, and this activation is often causative of tumorigenesis. We utilized the Gal4-UAS system in Drosophila imaginal primordia, highly proliferative and growing tissues, to analyze the impact of restricted activation of these pathways on neighboring wild-type cell populations. Activation of these pathways leads to an autonomous induction of tissue overgrowth and to a remarkable nonautonomous reduction in growth and proliferation rates of adjacent cell populations. This nonautonomous response occurs independently of where these pathways are activated, is functional all throughout development, takes place across compartments, and is distinct from cell competition. The observed autonomous and nonautonomous effects on tissue growth rely on the up-regulation of the proteoglycan Dally, a major element involved in modulating the spreading, stability, and activity of the growth promoting Decapentaplegic (Dpp)/transforming growth factor β(TGF-β) signaling molecule. Our findings indicate that a reduction in the amount of available growth factors contributes to the outcompetition of wild-type cells by overgrowing cell populations. During normal development, the PI3K/PTEN and TSC/TOR pathways play a major role in sensing nutrient availability and modulating the final size of any developing organ. We present evidence that Dally also contributes to integrating nutrient sensing and organ scaling, the fitting of pattern to size.

No MeSH data available.


Related in: MedlinePlus

Autonomous and nonautonomous effects on Dpp activity levels upon targeted activation of the PI3K/PTEN and TSC/TOR pathways.(A) Cuticle preparation of adult wings expressing GFP or Dp110 under the control of the ci-gal4 driver, which drives transgene expression in the anterior compartment. Note the expansion of the anterior intervein regions (blue arrows) upon induction of growth and the corresponding reduction of the posterior intervein regions (grey arrows). The anterior (A) and posterior (P) compartments are labeled, and the AP boundary is marked by a red line. (B) Wing imaginal disc of ci>GFP and ci>PTENRNAi larvae labelled to visualized Ci protein (in green) and β-galactosidase (βGal) (in red or white) to visualize dpp (dpp-lacZ) expression. The width of the dpp-lacZ stripe (normalized with respect to the width of the wing pouch) was ci>GFP = 0.082 ± 0.005; ci>PTENRNAi = 0.088 ± 0.003; p = 0.55; n > 6. (C) Wing imaginal discs of ci>GFP and ci>GFP, Dp110 larva labelled to visualize Spalt (in red) and GFP (in green) protein expression. The white dashed line marks the boundary between A and P cells. The lower panels show magnification of the Spalt domain. Note that the anterior Spalt domain is wider upon Dp110 expression (thick bracket) whereas the posterior Spalt domain (thin brackets) gets reduced. (D) Wing imaginal discs of ci>GFP and ci>GFP, Dp110 larva labelled to visualize pMAD protein (in red or white) and GFP (in green). Lower panels show magnifications of the pMAD domains, and the red line marks the boundary between the A and P compartments. Horizontal yellow lines were used to generate the pMAD profiles shown in E–I. (E, F, H, I) Average pMAD profiles of wing discs expressing GFP (red line) or GFP and the corresponding transgenes (blue line) under the control of the ci-gal4 driver. Profiles were taken along the AP axis and plotted in absolute positions. The standard error to the mean is shown in the corresponding color for each genotype. In E, the AP boundary of each experiment is marked by a dashed line of the corresponding color. In F, the AP boundary of both experiments was aligned to allow comparison of the profile in each compartment. Number of wing discs analyzed per genotype ≥ 5. The domains of transgene expression are marked with a black asterisk. Arrows mark the limits of the Dpp activity gradients. (G, J) Histograms plotting the total intensity of the pMAD signal in a.u. of the anterior (blue bars) and posterior (white bars) compartments of ci>GFP (G, J) and ci>Dp110 (G) or ci>Rheb (J) wing discs. Error bars indicate the standard deviation. Number of wing discs analyzed per genotype ≥ 5. ***p < 0.001. (K) Wing imaginal discs of nub>GFP and nub>Dp110 larvae labelled to visualize pMAD protein (in red), GFP (in green), and DAPI (in blue, to visualize nuclei). (L) Average pMAD profile of wing discs expressing GFP (red line) or Dp110 (blue line) in the nubbin domain. Profiles were taken along the AP axis and plotted in absolute positions. The standard error to the mean is shown in the corresponding color for each genotype. Number of wing discs analyzed per genotype ≥ 7. (M) Histogram plotting the total intensity of the pMAD signal in a.u. of the nubbin domain of nub>GFP (red bar) and nub>Dp110 (blue bar) discs. Error bars indicate the standard deviation. Number of wing discs analyzed per genotype ≥ 5. (N) Histogram plotting the area (in a.u.) of anterior (blue) and posterior (white) domains of wing discs expressing GFP or GFP and Dp110 in the ci domain. Error bars show the standard deviation. Number of wing discs analyzed per genotype ≥ 15. ***p < 0.001 (O) Histogram plotting the area (in a.u.) of anterior (blue) and posterior (white) domains of wing discs expressing either GFP or Dp110 in the ci domain together with a dsRNA form against dpp. Error bars show the standard deviation. Number of wing discs analyzed per genotype ≥ 15. ***p < 0.001, **p < 0.01. (P) Wing imaginal discs of ci>GFP and ci>dppRNAi larvae labelled to visualize GFP (in green) and DAPI (in blue, to visualize nuclei).
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pbio.1002239.g004: Autonomous and nonautonomous effects on Dpp activity levels upon targeted activation of the PI3K/PTEN and TSC/TOR pathways.(A) Cuticle preparation of adult wings expressing GFP or Dp110 under the control of the ci-gal4 driver, which drives transgene expression in the anterior compartment. Note the expansion of the anterior intervein regions (blue arrows) upon induction of growth and the corresponding reduction of the posterior intervein regions (grey arrows). The anterior (A) and posterior (P) compartments are labeled, and the AP boundary is marked by a red line. (B) Wing imaginal disc of ci>GFP and ci>PTENRNAi larvae labelled to visualized Ci protein (in green) and β-galactosidase (βGal) (in red or white) to visualize dpp (dpp-lacZ) expression. The width of the dpp-lacZ stripe (normalized with respect to the width of the wing pouch) was ci>GFP = 0.082 ± 0.005; ci>PTENRNAi = 0.088 ± 0.003; p = 0.55; n > 6. (C) Wing imaginal discs of ci>GFP and ci>GFP, Dp110 larva labelled to visualize Spalt (in red) and GFP (in green) protein expression. The white dashed line marks the boundary between A and P cells. The lower panels show magnification of the Spalt domain. Note that the anterior Spalt domain is wider upon Dp110 expression (thick bracket) whereas the posterior Spalt domain (thin brackets) gets reduced. (D) Wing imaginal discs of ci>GFP and ci>GFP, Dp110 larva labelled to visualize pMAD protein (in red or white) and GFP (in green). Lower panels show magnifications of the pMAD domains, and the red line marks the boundary between the A and P compartments. Horizontal yellow lines were used to generate the pMAD profiles shown in E–I. (E, F, H, I) Average pMAD profiles of wing discs expressing GFP (red line) or GFP and the corresponding transgenes (blue line) under the control of the ci-gal4 driver. Profiles were taken along the AP axis and plotted in absolute positions. The standard error to the mean is shown in the corresponding color for each genotype. In E, the AP boundary of each experiment is marked by a dashed line of the corresponding color. In F, the AP boundary of both experiments was aligned to allow comparison of the profile in each compartment. Number of wing discs analyzed per genotype ≥ 5. The domains of transgene expression are marked with a black asterisk. Arrows mark the limits of the Dpp activity gradients. (G, J) Histograms plotting the total intensity of the pMAD signal in a.u. of the anterior (blue bars) and posterior (white bars) compartments of ci>GFP (G, J) and ci>Dp110 (G) or ci>Rheb (J) wing discs. Error bars indicate the standard deviation. Number of wing discs analyzed per genotype ≥ 5. ***p < 0.001. (K) Wing imaginal discs of nub>GFP and nub>Dp110 larvae labelled to visualize pMAD protein (in red), GFP (in green), and DAPI (in blue, to visualize nuclei). (L) Average pMAD profile of wing discs expressing GFP (red line) or Dp110 (blue line) in the nubbin domain. Profiles were taken along the AP axis and plotted in absolute positions. The standard error to the mean is shown in the corresponding color for each genotype. Number of wing discs analyzed per genotype ≥ 7. (M) Histogram plotting the total intensity of the pMAD signal in a.u. of the nubbin domain of nub>GFP (red bar) and nub>Dp110 (blue bar) discs. Error bars indicate the standard deviation. Number of wing discs analyzed per genotype ≥ 5. (N) Histogram plotting the area (in a.u.) of anterior (blue) and posterior (white) domains of wing discs expressing GFP or GFP and Dp110 in the ci domain. Error bars show the standard deviation. Number of wing discs analyzed per genotype ≥ 15. ***p < 0.001 (O) Histogram plotting the area (in a.u.) of anterior (blue) and posterior (white) domains of wing discs expressing either GFP or Dp110 in the ci domain together with a dsRNA form against dpp. Error bars show the standard deviation. Number of wing discs analyzed per genotype ≥ 15. ***p < 0.001, **p < 0.01. (P) Wing imaginal discs of ci>GFP and ci>dppRNAi larvae labelled to visualize GFP (in green) and DAPI (in blue, to visualize nuclei).

Mentions: We noticed that activation of the PI3K/PTEN or TSC/TOR pathways in defined populations of the wing primordium gave rise to larger but well-proportioned adult structures (Fig 4A, see also Fig 1). The adjacent wild-type territories were reduced in size, but the patterning elements (e.g., longitudinal veins) were also proportionally well located. The signaling molecule Dpp, a member of the TGF-β superfamily, is expressed at the boundary between the A and P compartments in the developing wing (Fig 4B) and plays a major role in positioning the wing veins along the anterior–posterior axis [42]. Interestingly, the Dpp gradient scales with size in order to correctly maintain the wing proportions [43–46], and Dpp is well known to promote tissue growth (reviewed in [17,18]). Thus, the autonomous and nonautonomous effects of Rheb or Dp110/PI3K overexpression on tissue growth might rely on modulating the range of Dpp activity. Since dpp expression was largely unaffected in transgene-expressing tissues (Fig 4B), we monitored the range of the Dpp activity gradient, visualized by the expression of the Dpp target gene Spalt (Fig 4C, [47]) and with an antibody against the phosphorylated form of the Dpp transducer Mothers Against Dpp (pMAD, Fig 4D). As expected and as a result of the capacity of the Dpp gradient to scale with tissue size, the range of the Dpp activity gradient was expanded in the overgrowing transgene-expressing compartment (Fig 4C and 4D). In order to quantify the cell-autonomous impact of tissue growth on the Dpp activity gradient, we extracted the pMAD profiles along four lines perpendicular to the dpp expression domain (yellow lines in Fig 4D) and plotted the average pMAD values along the AP axis in experimental (blue in Fig 4E, 4F, 4H and 4I) and control (red in Fig 4E, 4F, 4H and 4I) wing primordia raised in the same conditions and immunolabeled in the same tube (as previously done in [45]). Since the boundary between A and P cells is out of phase in control and Dp110-expressing wing discs (Fig 4E), the pMAD profiles were aligned with respect to the AP boundary to better visualize the autonomous and nonautonomous effects on the Dpp activity gradient (Fig 4F and 4I). Despite the visible expansion along the AP axis of the pMAD gradient in the overgrowing compartment (black asterisk in Fig 4E, 4F and 4I, see also S2 Fig), the total amount of pMAD, quantified as total pixel intensity within each compartment (see Materials and Methods), was comparable in overgrowing and control compartments (Fig 4G and 4J, see also S2 Fig). A similar relationship between the range of the pMAD gradient and the total amount of pMAD was observed when transgene expression was driven in the whole wing primordium (Fig 4K–4M). These results indicate that tissue growth has a major impact in Dpp spreading but not signaling. Two observations suggest that the tissue-autonomous expansion of the pMAD gradient is a consequence of increased tissue size, and that this expansion is not solely a consequence of increased number of cells. First, Rheb overexpression increased tissue and cell size, but not cell number, and led to the expansion of the pMAD gradient (Fig 4I, black asterisk). Second, increased cell number without affecting tissue size (by means of expression of the cell cycle regulators CycE and String/Dcdc25) did not have any impact on the pMAD gradient (Fig 4H, black asterisk).


Dally Proteoglycan Mediates the Autonomous and Nonautonomous Effects on Tissue Growth Caused by Activation of the PI3K and TOR Pathways.

Ferreira A, Milán M - PLoS Biol. (2015)

Autonomous and nonautonomous effects on Dpp activity levels upon targeted activation of the PI3K/PTEN and TSC/TOR pathways.(A) Cuticle preparation of adult wings expressing GFP or Dp110 under the control of the ci-gal4 driver, which drives transgene expression in the anterior compartment. Note the expansion of the anterior intervein regions (blue arrows) upon induction of growth and the corresponding reduction of the posterior intervein regions (grey arrows). The anterior (A) and posterior (P) compartments are labeled, and the AP boundary is marked by a red line. (B) Wing imaginal disc of ci>GFP and ci>PTENRNAi larvae labelled to visualized Ci protein (in green) and β-galactosidase (βGal) (in red or white) to visualize dpp (dpp-lacZ) expression. The width of the dpp-lacZ stripe (normalized with respect to the width of the wing pouch) was ci>GFP = 0.082 ± 0.005; ci>PTENRNAi = 0.088 ± 0.003; p = 0.55; n > 6. (C) Wing imaginal discs of ci>GFP and ci>GFP, Dp110 larva labelled to visualize Spalt (in red) and GFP (in green) protein expression. The white dashed line marks the boundary between A and P cells. The lower panels show magnification of the Spalt domain. Note that the anterior Spalt domain is wider upon Dp110 expression (thick bracket) whereas the posterior Spalt domain (thin brackets) gets reduced. (D) Wing imaginal discs of ci>GFP and ci>GFP, Dp110 larva labelled to visualize pMAD protein (in red or white) and GFP (in green). Lower panels show magnifications of the pMAD domains, and the red line marks the boundary between the A and P compartments. Horizontal yellow lines were used to generate the pMAD profiles shown in E–I. (E, F, H, I) Average pMAD profiles of wing discs expressing GFP (red line) or GFP and the corresponding transgenes (blue line) under the control of the ci-gal4 driver. Profiles were taken along the AP axis and plotted in absolute positions. The standard error to the mean is shown in the corresponding color for each genotype. In E, the AP boundary of each experiment is marked by a dashed line of the corresponding color. In F, the AP boundary of both experiments was aligned to allow comparison of the profile in each compartment. Number of wing discs analyzed per genotype ≥ 5. The domains of transgene expression are marked with a black asterisk. Arrows mark the limits of the Dpp activity gradients. (G, J) Histograms plotting the total intensity of the pMAD signal in a.u. of the anterior (blue bars) and posterior (white bars) compartments of ci>GFP (G, J) and ci>Dp110 (G) or ci>Rheb (J) wing discs. Error bars indicate the standard deviation. Number of wing discs analyzed per genotype ≥ 5. ***p < 0.001. (K) Wing imaginal discs of nub>GFP and nub>Dp110 larvae labelled to visualize pMAD protein (in red), GFP (in green), and DAPI (in blue, to visualize nuclei). (L) Average pMAD profile of wing discs expressing GFP (red line) or Dp110 (blue line) in the nubbin domain. Profiles were taken along the AP axis and plotted in absolute positions. The standard error to the mean is shown in the corresponding color for each genotype. Number of wing discs analyzed per genotype ≥ 7. (M) Histogram plotting the total intensity of the pMAD signal in a.u. of the nubbin domain of nub>GFP (red bar) and nub>Dp110 (blue bar) discs. Error bars indicate the standard deviation. Number of wing discs analyzed per genotype ≥ 5. (N) Histogram plotting the area (in a.u.) of anterior (blue) and posterior (white) domains of wing discs expressing GFP or GFP and Dp110 in the ci domain. Error bars show the standard deviation. Number of wing discs analyzed per genotype ≥ 15. ***p < 0.001 (O) Histogram plotting the area (in a.u.) of anterior (blue) and posterior (white) domains of wing discs expressing either GFP or Dp110 in the ci domain together with a dsRNA form against dpp. Error bars show the standard deviation. Number of wing discs analyzed per genotype ≥ 15. ***p < 0.001, **p < 0.01. (P) Wing imaginal discs of ci>GFP and ci>dppRNAi larvae labelled to visualize GFP (in green) and DAPI (in blue, to visualize nuclei).
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pbio.1002239.g004: Autonomous and nonautonomous effects on Dpp activity levels upon targeted activation of the PI3K/PTEN and TSC/TOR pathways.(A) Cuticle preparation of adult wings expressing GFP or Dp110 under the control of the ci-gal4 driver, which drives transgene expression in the anterior compartment. Note the expansion of the anterior intervein regions (blue arrows) upon induction of growth and the corresponding reduction of the posterior intervein regions (grey arrows). The anterior (A) and posterior (P) compartments are labeled, and the AP boundary is marked by a red line. (B) Wing imaginal disc of ci>GFP and ci>PTENRNAi larvae labelled to visualized Ci protein (in green) and β-galactosidase (βGal) (in red or white) to visualize dpp (dpp-lacZ) expression. The width of the dpp-lacZ stripe (normalized with respect to the width of the wing pouch) was ci>GFP = 0.082 ± 0.005; ci>PTENRNAi = 0.088 ± 0.003; p = 0.55; n > 6. (C) Wing imaginal discs of ci>GFP and ci>GFP, Dp110 larva labelled to visualize Spalt (in red) and GFP (in green) protein expression. The white dashed line marks the boundary between A and P cells. The lower panels show magnification of the Spalt domain. Note that the anterior Spalt domain is wider upon Dp110 expression (thick bracket) whereas the posterior Spalt domain (thin brackets) gets reduced. (D) Wing imaginal discs of ci>GFP and ci>GFP, Dp110 larva labelled to visualize pMAD protein (in red or white) and GFP (in green). Lower panels show magnifications of the pMAD domains, and the red line marks the boundary between the A and P compartments. Horizontal yellow lines were used to generate the pMAD profiles shown in E–I. (E, F, H, I) Average pMAD profiles of wing discs expressing GFP (red line) or GFP and the corresponding transgenes (blue line) under the control of the ci-gal4 driver. Profiles were taken along the AP axis and plotted in absolute positions. The standard error to the mean is shown in the corresponding color for each genotype. In E, the AP boundary of each experiment is marked by a dashed line of the corresponding color. In F, the AP boundary of both experiments was aligned to allow comparison of the profile in each compartment. Number of wing discs analyzed per genotype ≥ 5. The domains of transgene expression are marked with a black asterisk. Arrows mark the limits of the Dpp activity gradients. (G, J) Histograms plotting the total intensity of the pMAD signal in a.u. of the anterior (blue bars) and posterior (white bars) compartments of ci>GFP (G, J) and ci>Dp110 (G) or ci>Rheb (J) wing discs. Error bars indicate the standard deviation. Number of wing discs analyzed per genotype ≥ 5. ***p < 0.001. (K) Wing imaginal discs of nub>GFP and nub>Dp110 larvae labelled to visualize pMAD protein (in red), GFP (in green), and DAPI (in blue, to visualize nuclei). (L) Average pMAD profile of wing discs expressing GFP (red line) or Dp110 (blue line) in the nubbin domain. Profiles were taken along the AP axis and plotted in absolute positions. The standard error to the mean is shown in the corresponding color for each genotype. Number of wing discs analyzed per genotype ≥ 7. (M) Histogram plotting the total intensity of the pMAD signal in a.u. of the nubbin domain of nub>GFP (red bar) and nub>Dp110 (blue bar) discs. Error bars indicate the standard deviation. Number of wing discs analyzed per genotype ≥ 5. (N) Histogram plotting the area (in a.u.) of anterior (blue) and posterior (white) domains of wing discs expressing GFP or GFP and Dp110 in the ci domain. Error bars show the standard deviation. Number of wing discs analyzed per genotype ≥ 15. ***p < 0.001 (O) Histogram plotting the area (in a.u.) of anterior (blue) and posterior (white) domains of wing discs expressing either GFP or Dp110 in the ci domain together with a dsRNA form against dpp. Error bars show the standard deviation. Number of wing discs analyzed per genotype ≥ 15. ***p < 0.001, **p < 0.01. (P) Wing imaginal discs of ci>GFP and ci>dppRNAi larvae labelled to visualize GFP (in green) and DAPI (in blue, to visualize nuclei).
Mentions: We noticed that activation of the PI3K/PTEN or TSC/TOR pathways in defined populations of the wing primordium gave rise to larger but well-proportioned adult structures (Fig 4A, see also Fig 1). The adjacent wild-type territories were reduced in size, but the patterning elements (e.g., longitudinal veins) were also proportionally well located. The signaling molecule Dpp, a member of the TGF-β superfamily, is expressed at the boundary between the A and P compartments in the developing wing (Fig 4B) and plays a major role in positioning the wing veins along the anterior–posterior axis [42]. Interestingly, the Dpp gradient scales with size in order to correctly maintain the wing proportions [43–46], and Dpp is well known to promote tissue growth (reviewed in [17,18]). Thus, the autonomous and nonautonomous effects of Rheb or Dp110/PI3K overexpression on tissue growth might rely on modulating the range of Dpp activity. Since dpp expression was largely unaffected in transgene-expressing tissues (Fig 4B), we monitored the range of the Dpp activity gradient, visualized by the expression of the Dpp target gene Spalt (Fig 4C, [47]) and with an antibody against the phosphorylated form of the Dpp transducer Mothers Against Dpp (pMAD, Fig 4D). As expected and as a result of the capacity of the Dpp gradient to scale with tissue size, the range of the Dpp activity gradient was expanded in the overgrowing transgene-expressing compartment (Fig 4C and 4D). In order to quantify the cell-autonomous impact of tissue growth on the Dpp activity gradient, we extracted the pMAD profiles along four lines perpendicular to the dpp expression domain (yellow lines in Fig 4D) and plotted the average pMAD values along the AP axis in experimental (blue in Fig 4E, 4F, 4H and 4I) and control (red in Fig 4E, 4F, 4H and 4I) wing primordia raised in the same conditions and immunolabeled in the same tube (as previously done in [45]). Since the boundary between A and P cells is out of phase in control and Dp110-expressing wing discs (Fig 4E), the pMAD profiles were aligned with respect to the AP boundary to better visualize the autonomous and nonautonomous effects on the Dpp activity gradient (Fig 4F and 4I). Despite the visible expansion along the AP axis of the pMAD gradient in the overgrowing compartment (black asterisk in Fig 4E, 4F and 4I, see also S2 Fig), the total amount of pMAD, quantified as total pixel intensity within each compartment (see Materials and Methods), was comparable in overgrowing and control compartments (Fig 4G and 4J, see also S2 Fig). A similar relationship between the range of the pMAD gradient and the total amount of pMAD was observed when transgene expression was driven in the whole wing primordium (Fig 4K–4M). These results indicate that tissue growth has a major impact in Dpp spreading but not signaling. Two observations suggest that the tissue-autonomous expansion of the pMAD gradient is a consequence of increased tissue size, and that this expansion is not solely a consequence of increased number of cells. First, Rheb overexpression increased tissue and cell size, but not cell number, and led to the expansion of the pMAD gradient (Fig 4I, black asterisk). Second, increased cell number without affecting tissue size (by means of expression of the cell cycle regulators CycE and String/Dcdc25) did not have any impact on the pMAD gradient (Fig 4H, black asterisk).

Bottom Line: Activation of these pathways leads to an autonomous induction of tissue overgrowth and to a remarkable nonautonomous reduction in growth and proliferation rates of adjacent cell populations.The observed autonomous and nonautonomous effects on tissue growth rely on the up-regulation of the proteoglycan Dally, a major element involved in modulating the spreading, stability, and activity of the growth promoting Decapentaplegic (Dpp)/transforming growth factor β(TGF-β) signaling molecule.Our findings indicate that a reduction in the amount of available growth factors contributes to the outcompetition of wild-type cells by overgrowing cell populations.

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.

ABSTRACT
How cells acquiring mutations in tumor suppressor genes outcompete neighboring wild-type cells is poorly understood. The phosphatidylinositol 3-kinase (PI3K)-phosphatase with tensin homology (PTEN) and tuberous sclerosis complex (TSC)-target of rapamycin (TOR) pathways are frequently activated in human cancer, and this activation is often causative of tumorigenesis. We utilized the Gal4-UAS system in Drosophila imaginal primordia, highly proliferative and growing tissues, to analyze the impact of restricted activation of these pathways on neighboring wild-type cell populations. Activation of these pathways leads to an autonomous induction of tissue overgrowth and to a remarkable nonautonomous reduction in growth and proliferation rates of adjacent cell populations. This nonautonomous response occurs independently of where these pathways are activated, is functional all throughout development, takes place across compartments, and is distinct from cell competition. The observed autonomous and nonautonomous effects on tissue growth rely on the up-regulation of the proteoglycan Dally, a major element involved in modulating the spreading, stability, and activity of the growth promoting Decapentaplegic (Dpp)/transforming growth factor β(TGF-β) signaling molecule. Our findings indicate that a reduction in the amount of available growth factors contributes to the outcompetition of wild-type cells by overgrowing cell populations. During normal development, the PI3K/PTEN and TSC/TOR pathways play a major role in sensing nutrient availability and modulating the final size of any developing organ. We present evidence that Dally also contributes to integrating nutrient sensing and organ scaling, the fitting of pattern to size.

No MeSH data available.


Related in: MedlinePlus