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Scaling the Drosophila Wing: TOR-Dependent Target Gene Access by the Hippo Pathway Transducer Yorkie.

Parker J, Struhl G - PLoS Biol. (2015)

Bottom Line: Here, we show that the TOR pathway regulates Yki by a separate and novel mechanism in the Drosophila wing.Instead of controlling Yki nuclear access, TOR signaling governs Yki action after it reaches the nucleus by allowing it to gain access to its target genes.When TOR activity is inhibited, Yki accumulates in the nucleus but is sequestered from its normal growth-promoting target genes--a phenomenon we term "nuclear seclusion." Hence, we posit that in addition to its well-known role in stimulating cellular metabolism in response to nutrients, TOR also promotes wing growth by liberating Yki from nuclear seclusion, a parallel pathway that we propose contributes to the scaling of wing size with nutrient availability.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Development, Columbia University, New York, New York, United States of America; Division of Biology, Imperial College London, London, United Kingdom.

ABSTRACT
Organ growth is controlled by patterning signals that operate locally (e.g., Wingless/Ints [Wnts], Bone Morphogenetic Proteins [BMPs], and Hedgehogs [Hhs]) and scaled by nutrient-dependent signals that act systemically (e.g., Insulin-like peptides [ILPs] transduced by the Target of Rapamycin [TOR] pathway). How cells integrate these distinct inputs to generate organs of the appropriate size and shape is largely unknown. The transcriptional coactivator Yorkie (Yki, a YES-Associated Protein, or YAP) acts downstream of patterning morphogens and other tissue-intrinsic signals to promote organ growth. Yki activity is regulated primarily by the Warts/Hippo (Wts/Hpo) tumour suppressor pathway, which impedes nuclear access of Yki by a cytoplasmic tethering mechanism. Here, we show that the TOR pathway regulates Yki by a separate and novel mechanism in the Drosophila wing. Instead of controlling Yki nuclear access, TOR signaling governs Yki action after it reaches the nucleus by allowing it to gain access to its target genes. When TOR activity is inhibited, Yki accumulates in the nucleus but is sequestered from its normal growth-promoting target genes--a phenomenon we term "nuclear seclusion." Hence, we posit that in addition to its well-known role in stimulating cellular metabolism in response to nutrients, TOR also promotes wing growth by liberating Yki from nuclear seclusion, a parallel pathway that we propose contributes to the scaling of wing size with nutrient availability.

No MeSH data available.


Related in: MedlinePlus

Integrating Yki-dependent wing growth with InR/TOR pathway activity.(A) Under normal physiological conditions (left panel), Yki shuttles between the nucleus and cytoplasm in response to phosphorylation (P) by Wts, which targets Yki to cytosolic tethers. Wing disc intrinsic signals (e.g., the morphogens Dpp and Wg) drive wing growth by down-regulating Wts activity, allowing a small proportion of Yki to escape phosphorylation-dependent tethering, enter the nucleus, and bind to its growth-promoting target genes in complex with Sd. Inhibiting the InR/TOR pathway results in up-regulation or activation of a putative NSF that sequesters unphosphorylated Yki in the nucleus and impedes binding of the Yki-Sd complex to its target genes, reducing Yki-Sd dependent growth. (B) Proposed integration of InR/TOR and Wts/Yki signaling to scale wing growth. In well-fed animals (left panel), TOR activation by wing disc extrinsic, nutrient-dependent signals facilitates Yki-dependent tissue growth by two parallel means: (i) by inhibiting NSF and thereby potentiating Yki nuclear access and target gene expression, and (ii), by up-regulating cell physiological functions such as dS6-Kinase and possibly many others, to match growth potential to the level of Yki target gene activity. Reductions in InR/TOR activity diminish both outputs, leading to reduced cell proliferation and tissue growth. (C) Excess growth caused by superphysiological activation of TOR is offset by Yki-independent down-regulation of the antiapoptotic factors DIAP1 and bantam, promoting cell death and safeguarding the developing wing against hyperplasia.
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pbio.1002274.g007: Integrating Yki-dependent wing growth with InR/TOR pathway activity.(A) Under normal physiological conditions (left panel), Yki shuttles between the nucleus and cytoplasm in response to phosphorylation (P) by Wts, which targets Yki to cytosolic tethers. Wing disc intrinsic signals (e.g., the morphogens Dpp and Wg) drive wing growth by down-regulating Wts activity, allowing a small proportion of Yki to escape phosphorylation-dependent tethering, enter the nucleus, and bind to its growth-promoting target genes in complex with Sd. Inhibiting the InR/TOR pathway results in up-regulation or activation of a putative NSF that sequesters unphosphorylated Yki in the nucleus and impedes binding of the Yki-Sd complex to its target genes, reducing Yki-Sd dependent growth. (B) Proposed integration of InR/TOR and Wts/Yki signaling to scale wing growth. In well-fed animals (left panel), TOR activation by wing disc extrinsic, nutrient-dependent signals facilitates Yki-dependent tissue growth by two parallel means: (i) by inhibiting NSF and thereby potentiating Yki nuclear access and target gene expression, and (ii), by up-regulating cell physiological functions such as dS6-Kinase and possibly many others, to match growth potential to the level of Yki target gene activity. Reductions in InR/TOR activity diminish both outputs, leading to reduced cell proliferation and tissue growth. (C) Excess growth caused by superphysiological activation of TOR is offset by Yki-independent down-regulation of the antiapoptotic factors DIAP1 and bantam, promoting cell death and safeguarding the developing wing against hyperplasia.

Mentions: Based on our results, and as summarised in Fig 7A, we propose that reduced TOR signaling causes Yki to bind a secluding factor that sequesters Yki in the nucleus but diverts it from acting in complex with Sd to bind target loci, thereby reducing gene transcription. We posit that, by combining TOR-dependent relief from Yki nuclear seclusion with canonical Wts/Hpo phosphoregulation of Yki nuclear access, wing cells are able to integrate nutrient levels (via TOR) with patterning/morphogenetic inputs (via Wts/Hpo) to achieve a level of Yki-Sd activity that matches metabolic capacity and scales wing size appropriately. Elucidating this mechanism further will depend on identifying the proposed NSF and determining how its action is mediated by Yki’s N-terminus and WW domains. NSF may bind Yki that shuttles into the nucleus, titrating it away from target genes; one possibility, raised by a reviewer, is that NSF acts by modifying Yki in some way, stabilizing the protein and preventing its degradation (thereby contributing to its observed accumulation in the nucleus) with a modification that blocks it from accessing target loci.


Scaling the Drosophila Wing: TOR-Dependent Target Gene Access by the Hippo Pathway Transducer Yorkie.

Parker J, Struhl G - PLoS Biol. (2015)

Integrating Yki-dependent wing growth with InR/TOR pathway activity.(A) Under normal physiological conditions (left panel), Yki shuttles between the nucleus and cytoplasm in response to phosphorylation (P) by Wts, which targets Yki to cytosolic tethers. Wing disc intrinsic signals (e.g., the morphogens Dpp and Wg) drive wing growth by down-regulating Wts activity, allowing a small proportion of Yki to escape phosphorylation-dependent tethering, enter the nucleus, and bind to its growth-promoting target genes in complex with Sd. Inhibiting the InR/TOR pathway results in up-regulation or activation of a putative NSF that sequesters unphosphorylated Yki in the nucleus and impedes binding of the Yki-Sd complex to its target genes, reducing Yki-Sd dependent growth. (B) Proposed integration of InR/TOR and Wts/Yki signaling to scale wing growth. In well-fed animals (left panel), TOR activation by wing disc extrinsic, nutrient-dependent signals facilitates Yki-dependent tissue growth by two parallel means: (i) by inhibiting NSF and thereby potentiating Yki nuclear access and target gene expression, and (ii), by up-regulating cell physiological functions such as dS6-Kinase and possibly many others, to match growth potential to the level of Yki target gene activity. Reductions in InR/TOR activity diminish both outputs, leading to reduced cell proliferation and tissue growth. (C) Excess growth caused by superphysiological activation of TOR is offset by Yki-independent down-regulation of the antiapoptotic factors DIAP1 and bantam, promoting cell death and safeguarding the developing wing against hyperplasia.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608745&req=5

pbio.1002274.g007: Integrating Yki-dependent wing growth with InR/TOR pathway activity.(A) Under normal physiological conditions (left panel), Yki shuttles between the nucleus and cytoplasm in response to phosphorylation (P) by Wts, which targets Yki to cytosolic tethers. Wing disc intrinsic signals (e.g., the morphogens Dpp and Wg) drive wing growth by down-regulating Wts activity, allowing a small proportion of Yki to escape phosphorylation-dependent tethering, enter the nucleus, and bind to its growth-promoting target genes in complex with Sd. Inhibiting the InR/TOR pathway results in up-regulation or activation of a putative NSF that sequesters unphosphorylated Yki in the nucleus and impedes binding of the Yki-Sd complex to its target genes, reducing Yki-Sd dependent growth. (B) Proposed integration of InR/TOR and Wts/Yki signaling to scale wing growth. In well-fed animals (left panel), TOR activation by wing disc extrinsic, nutrient-dependent signals facilitates Yki-dependent tissue growth by two parallel means: (i) by inhibiting NSF and thereby potentiating Yki nuclear access and target gene expression, and (ii), by up-regulating cell physiological functions such as dS6-Kinase and possibly many others, to match growth potential to the level of Yki target gene activity. Reductions in InR/TOR activity diminish both outputs, leading to reduced cell proliferation and tissue growth. (C) Excess growth caused by superphysiological activation of TOR is offset by Yki-independent down-regulation of the antiapoptotic factors DIAP1 and bantam, promoting cell death and safeguarding the developing wing against hyperplasia.
Mentions: Based on our results, and as summarised in Fig 7A, we propose that reduced TOR signaling causes Yki to bind a secluding factor that sequesters Yki in the nucleus but diverts it from acting in complex with Sd to bind target loci, thereby reducing gene transcription. We posit that, by combining TOR-dependent relief from Yki nuclear seclusion with canonical Wts/Hpo phosphoregulation of Yki nuclear access, wing cells are able to integrate nutrient levels (via TOR) with patterning/morphogenetic inputs (via Wts/Hpo) to achieve a level of Yki-Sd activity that matches metabolic capacity and scales wing size appropriately. Elucidating this mechanism further will depend on identifying the proposed NSF and determining how its action is mediated by Yki’s N-terminus and WW domains. NSF may bind Yki that shuttles into the nucleus, titrating it away from target genes; one possibility, raised by a reviewer, is that NSF acts by modifying Yki in some way, stabilizing the protein and preventing its degradation (thereby contributing to its observed accumulation in the nucleus) with a modification that blocks it from accessing target loci.

Bottom Line: Here, we show that the TOR pathway regulates Yki by a separate and novel mechanism in the Drosophila wing.Instead of controlling Yki nuclear access, TOR signaling governs Yki action after it reaches the nucleus by allowing it to gain access to its target genes.When TOR activity is inhibited, Yki accumulates in the nucleus but is sequestered from its normal growth-promoting target genes--a phenomenon we term "nuclear seclusion." Hence, we posit that in addition to its well-known role in stimulating cellular metabolism in response to nutrients, TOR also promotes wing growth by liberating Yki from nuclear seclusion, a parallel pathway that we propose contributes to the scaling of wing size with nutrient availability.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Development, Columbia University, New York, New York, United States of America; Division of Biology, Imperial College London, London, United Kingdom.

ABSTRACT
Organ growth is controlled by patterning signals that operate locally (e.g., Wingless/Ints [Wnts], Bone Morphogenetic Proteins [BMPs], and Hedgehogs [Hhs]) and scaled by nutrient-dependent signals that act systemically (e.g., Insulin-like peptides [ILPs] transduced by the Target of Rapamycin [TOR] pathway). How cells integrate these distinct inputs to generate organs of the appropriate size and shape is largely unknown. The transcriptional coactivator Yorkie (Yki, a YES-Associated Protein, or YAP) acts downstream of patterning morphogens and other tissue-intrinsic signals to promote organ growth. Yki activity is regulated primarily by the Warts/Hippo (Wts/Hpo) tumour suppressor pathway, which impedes nuclear access of Yki by a cytoplasmic tethering mechanism. Here, we show that the TOR pathway regulates Yki by a separate and novel mechanism in the Drosophila wing. Instead of controlling Yki nuclear access, TOR signaling governs Yki action after it reaches the nucleus by allowing it to gain access to its target genes. When TOR activity is inhibited, Yki accumulates in the nucleus but is sequestered from its normal growth-promoting target genes--a phenomenon we term "nuclear seclusion." Hence, we posit that in addition to its well-known role in stimulating cellular metabolism in response to nutrients, TOR also promotes wing growth by liberating Yki from nuclear seclusion, a parallel pathway that we propose contributes to the scaling of wing size with nutrient availability.

No MeSH data available.


Related in: MedlinePlus