Hippo signaling instructs ectopic but not normal organ growth

W Kowalczyk; L Romanelli; M Atkins; H Hillen; C Bravo González-Blas; J Jacobs; J Xie; S Soheily; E Verboven; I M Moya; S Verhulst; M de Waegeneer; L Sansores-Garcia; L van Huffel; R L Johnson; L A van Grunsven; S Aerts; G Halder

doi:10.1126/science.abg3679

Hippo signaling instructs ectopic but not normal organ growth

W Kowalczyk, L Romanelli, M Atkins, H Hillen, C Bravo González-Blas, J Jacobs, J Xie, S Soheily, E Verboven, I M Moya, S Verhulst, M de Waegeneer, L Sansores-Garcia, L van Huffel, R L Johnson, L A van Grunsven, S Aerts, G Halder

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Abstract

The Hippo signaling pathway is widely considered a master regulator of organ growth because of the prominent overgrowth phenotypes caused by experimental manipulation of its activity. Contrary to this model, we show here that removing Hippo transcriptional output did not impair the ability of the mouse liver and Drosophila eyes to grow to their normal size. Moreover, the transcriptional activity of the Hippo pathway effectors Yap/Taz/Yki did not correlate with cell proliferation, and hyperactivation of these effectors induced gene expression programs that did not recapitulate normal development. Concordantly, a functional screen in Drosophila identified several Hippo pathway target genes that were required for ectopic overgrowth but not normal growth. Thus, Hippo signaling does not instruct normal growth, and the Hippo-induced overgrowth phenotypes are caused by the activation of abnormal genetic programs.

Original language	English
Pages (from-to)	eabg3679
Journal	Science
Volume	378
Issue number	6621
DOIs	https://doi.org/10.1126/science.abg3679
Publication status	Published - 18 Nov 2022

Bibliographical note

Funding Information:
This work was supported by The Research Foundation Flanders (FWO Odysseus type I grant and project grants G.0954.16N and G.030616N to G.H. and an FWO doctoral fellowship to W.K.) and by the Cancer Prevention and Research Institute of Texas (grant RP200240 to R.J.).

Publisher Copyright:
© 2022 American Association for the Advancement of Science. All rights reserved.

Copyright:
Copyright 2022 Elsevier B.V., All rights reserved.

Keywords

Animals
Mice
Drosophila melanogaster/embryology
Drosophila Proteins/genetics
Eye/embryology
Gene Expression Regulation, Developmental
Hippo Signaling Pathway/genetics
Liver/embryology
Organ Size
Protein Serine-Threonine Kinases/genetics
Trans-Activators/genetics
Transcription, Genetic
Transcriptional Coactivator with PDZ-Binding Motif Proteins/metabolism
YAP-Signaling Proteins/metabolism

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Hippo signaling instructs ectopic but not normal organ growthAccepted author manuscript, 45.8 MB

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Kowalczyk, W., Romanelli, L., Atkins, M., Hillen, H., Bravo González-Blas, C., Jacobs, J., Xie, J., Soheily, S., Verboven, E., Moya, I. M., Verhulst, S., de Waegeneer, M., Sansores-Garcia, L., van Huffel, L., Johnson, R. L., van Grunsven, L. A., Aerts, S., & Halder, G. (2022). Hippo signaling instructs ectopic but not normal organ growth. Science, 378(6621), eabg3679. https://doi.org/10.1126/science.abg3679

@article{d38de71496184638a5484dd5f8bd5000,

title = "Hippo signaling instructs ectopic but not normal organ growth",

abstract = "The Hippo signaling pathway is widely considered a master regulator of organ growth because of the prominent overgrowth phenotypes caused by experimental manipulation of its activity. Contrary to this model, we show here that removing Hippo transcriptional output did not impair the ability of the mouse liver and Drosophila eyes to grow to their normal size. Moreover, the transcriptional activity of the Hippo pathway effectors Yap/Taz/Yki did not correlate with cell proliferation, and hyperactivation of these effectors induced gene expression programs that did not recapitulate normal development. Concordantly, a functional screen in Drosophila identified several Hippo pathway target genes that were required for ectopic overgrowth but not normal growth. Thus, Hippo signaling does not instruct normal growth, and the Hippo-induced overgrowth phenotypes are caused by the activation of abnormal genetic programs.",

keywords = "Animals, Mice, Drosophila melanogaster/embryology, Drosophila Proteins/genetics, Eye/embryology, Gene Expression Regulation, Developmental, Hippo Signaling Pathway/genetics, Liver/embryology, Organ Size, Protein Serine-Threonine Kinases/genetics, Trans-Activators/genetics, Transcription, Genetic, Transcriptional Coactivator with PDZ-Binding Motif Proteins/metabolism, YAP-Signaling Proteins/metabolism",

author = "W Kowalczyk and L Romanelli and M Atkins and H Hillen and {Bravo Gonz{\'a}lez-Blas}, C and J Jacobs and J Xie and S Soheily and E Verboven and Moya, {I M} and S Verhulst and {de Waegeneer}, M and L Sansores-Garcia and {van Huffel}, L and Johnson, {R L} and {van Grunsven}, {L A} and S Aerts and G Halder",

note = "Funding Information: This work was supported by The Research Foundation Flanders (FWO Odysseus type I grant and project grants G.0954.16N and G.030616N to G.H. and an FWO doctoral fellowship to W.K.) and by the Cancer Prevention and Research Institute of Texas (grant RP200240 to R.J.). Publisher Copyright: {\textcopyright} 2022 American Association for the Advancement of Science. All rights reserved. Copyright: Copyright 2022 Elsevier B.V., All rights reserved.",

year = "2022",

month = nov,

day = "18",

doi = "10.1126/science.abg3679",

language = "English",

volume = "378",

pages = "eabg3679",

journal = "Science",

issn = "0036-8075",

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Kowalczyk, W, Romanelli, L, Atkins, M, Hillen, H, Bravo González-Blas, C, Jacobs, J, Xie, J, Soheily, S, Verboven, E, Moya, IM, Verhulst, S, de Waegeneer, M, Sansores-Garcia, L, van Huffel, L, Johnson, RL, van Grunsven, LA, Aerts, S & Halder, G 2022, 'Hippo signaling instructs ectopic but not normal organ growth', Science, vol. 378, no. 6621, pp. eabg3679. https://doi.org/10.1126/science.abg3679

TY - JOUR

T1 - Hippo signaling instructs ectopic but not normal organ growth

AU - Kowalczyk, W

AU - Romanelli, L

AU - Atkins, M

AU - Hillen, H

AU - Bravo González-Blas, C

AU - Jacobs, J

AU - Xie, J

AU - Soheily, S

AU - Verboven, E

AU - Moya, I M

AU - Verhulst, S

AU - de Waegeneer, M

AU - Sansores-Garcia, L

AU - van Huffel, L

AU - Johnson, R L

AU - van Grunsven, L A

AU - Aerts, S

AU - Halder, G

N1 - Funding Information: This work was supported by The Research Foundation Flanders (FWO Odysseus type I grant and project grants G.0954.16N and G.030616N to G.H. and an FWO doctoral fellowship to W.K.) and by the Cancer Prevention and Research Institute of Texas (grant RP200240 to R.J.). Publisher Copyright: © 2022 American Association for the Advancement of Science. All rights reserved. Copyright: Copyright 2022 Elsevier B.V., All rights reserved.

PY - 2022/11/18

Y1 - 2022/11/18

N2 - The Hippo signaling pathway is widely considered a master regulator of organ growth because of the prominent overgrowth phenotypes caused by experimental manipulation of its activity. Contrary to this model, we show here that removing Hippo transcriptional output did not impair the ability of the mouse liver and Drosophila eyes to grow to their normal size. Moreover, the transcriptional activity of the Hippo pathway effectors Yap/Taz/Yki did not correlate with cell proliferation, and hyperactivation of these effectors induced gene expression programs that did not recapitulate normal development. Concordantly, a functional screen in Drosophila identified several Hippo pathway target genes that were required for ectopic overgrowth but not normal growth. Thus, Hippo signaling does not instruct normal growth, and the Hippo-induced overgrowth phenotypes are caused by the activation of abnormal genetic programs.

AB - The Hippo signaling pathway is widely considered a master regulator of organ growth because of the prominent overgrowth phenotypes caused by experimental manipulation of its activity. Contrary to this model, we show here that removing Hippo transcriptional output did not impair the ability of the mouse liver and Drosophila eyes to grow to their normal size. Moreover, the transcriptional activity of the Hippo pathway effectors Yap/Taz/Yki did not correlate with cell proliferation, and hyperactivation of these effectors induced gene expression programs that did not recapitulate normal development. Concordantly, a functional screen in Drosophila identified several Hippo pathway target genes that were required for ectopic overgrowth but not normal growth. Thus, Hippo signaling does not instruct normal growth, and the Hippo-induced overgrowth phenotypes are caused by the activation of abnormal genetic programs.

KW - Animals

KW - Mice

KW - Drosophila melanogaster/embryology

KW - Drosophila Proteins/genetics

KW - Eye/embryology

KW - Gene Expression Regulation, Developmental

KW - Hippo Signaling Pathway/genetics

KW - Liver/embryology

KW - Organ Size

KW - Protein Serine-Threonine Kinases/genetics

KW - Trans-Activators/genetics

KW - Transcription, Genetic

KW - Transcriptional Coactivator with PDZ-Binding Motif Proteins/metabolism

KW - YAP-Signaling Proteins/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85142177521&partnerID=8YFLogxK

U2 - 10.1126/science.abg3679

DO - 10.1126/science.abg3679

M3 - Article

C2 - 36395225

SN - 0036-8075

VL - 378

SP - eabg3679

JO - Science

JF - Science

IS - 6621

ER -

Hippo signaling instructs ectopic but not normal organ growth

Abstract

Bibliographical note

Keywords

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