FoxOs Cooperatively Regulate Diverse Pathways Governing Neural Stem Cell Homeostasis

Ji hye Paik; Zhihu Ding; Rujuta Narurkar; Shakti Ramkissoon; Florian Muller; Walid S. Kamoun; Sung Suk Chae; Hongwu Zheng; Haoqiang Ying; Jed Mahoney; David Hiller; Shan Jiang; Alexei Protopopov; Wing H. Wong; Lynda Chin; Keith L. Ligon; Ronald A. DePinho

doi:10.1016/j.stem.2009.09.013

FoxOs Cooperatively Regulate Diverse Pathways Governing Neural Stem Cell Homeostasis

Ji hye Paik, Zhihu Ding, Rujuta Narurkar, Shakti Ramkissoon, Florian Muller, Walid S. Kamoun, Sung Suk Chae, Hongwu Zheng, Haoqiang Ying, Jed Mahoney, David Hiller, Shan Jiang, Alexei Protopopov, Wing H. Wong, Lynda Chin, Keith L. Ligon, Ronald A. DePinho

Genomic Medicine

Research output: Contribution to journal › Article › peer-review

378 Scopus citations

Abstract

The PI3K-AKT-FoxO pathway is integral to lifespan regulation in lower organisms and essential for the stability of long-lived cells in mammals. Here, we report the impact of combined FoxO1, 3, and 4 deficiencies on mammalian brain physiology with a particular emphasis on the study of the neural stem/progenitor cell (NSC) pool. We show that the FoxO family plays a prominent role in NSC proliferation and renewal. FoxO-deficient mice show initial increased brain size and proliferation of neural progenitor cells during early postnatal life, followed by precocious significant decline in the NSC pool and accompanying neurogenesis in adult brains. Mechanistically, integrated transcriptomic, promoter, and functional analyses of FoxO-deficient NSC cultures identified direct gene targets with known links to the regulation of human brain size and the control of cellular proliferation, differentiation, and oxidative defense. Thus, the FoxO family coordinately regulates diverse genes and pathways to govern key aspects of NSC homeostasis in the mammalian brain.

Original language	English (US)
Pages (from-to)	540-553
Number of pages	14
Journal	Cell Stem Cell
Volume	5
Issue number	5
DOIs	https://doi.org/10.1016/j.stem.2009.09.013
State	Published - Nov 6 2009

Keywords

STEMCELL

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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10.1016/j.stem.2009.09.013

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Paik, J. H., Ding, Z., Narurkar, R., Ramkissoon, S., Muller, F., Kamoun, W. S., Chae, S. S., Zheng, H., Ying, H., Mahoney, J., Hiller, D., Jiang, S., Protopopov, A., Wong, W. H., Chin, L., Ligon, K. L., & DePinho, R. A. (2009). FoxOs Cooperatively Regulate Diverse Pathways Governing Neural Stem Cell Homeostasis. Cell Stem Cell, 5(5), 540-553. https://doi.org/10.1016/j.stem.2009.09.013

Paik, JH, Ding, Z, Narurkar, R, Ramkissoon, S, Muller, F, Kamoun, WS, Chae, SS, Zheng, H, Ying, H, Mahoney, J, Hiller, D, Jiang, S, Protopopov, A, Wong, WH, Chin, L, Ligon, KL & DePinho, RA 2009, 'FoxOs Cooperatively Regulate Diverse Pathways Governing Neural Stem Cell Homeostasis', Cell Stem Cell, vol. 5, no. 5, pp. 540-553. https://doi.org/10.1016/j.stem.2009.09.013

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title = "FoxOs Cooperatively Regulate Diverse Pathways Governing Neural Stem Cell Homeostasis",

abstract = "The PI3K-AKT-FoxO pathway is integral to lifespan regulation in lower organisms and essential for the stability of long-lived cells in mammals. Here, we report the impact of combined FoxO1, 3, and 4 deficiencies on mammalian brain physiology with a particular emphasis on the study of the neural stem/progenitor cell (NSC) pool. We show that the FoxO family plays a prominent role in NSC proliferation and renewal. FoxO-deficient mice show initial increased brain size and proliferation of neural progenitor cells during early postnatal life, followed by precocious significant decline in the NSC pool and accompanying neurogenesis in adult brains. Mechanistically, integrated transcriptomic, promoter, and functional analyses of FoxO-deficient NSC cultures identified direct gene targets with known links to the regulation of human brain size and the control of cellular proliferation, differentiation, and oxidative defense. Thus, the FoxO family coordinately regulates diverse genes and pathways to govern key aspects of NSC homeostasis in the mammalian brain.",

keywords = "STEMCELL",

author = "Paik, {Ji hye} and Zhihu Ding and Rujuta Narurkar and Shakti Ramkissoon and Florian Muller and Kamoun, {Walid S.} and Chae, {Sung Suk} and Hongwu Zheng and Haoqiang Ying and Jed Mahoney and David Hiller and Shan Jiang and Alexei Protopopov and Wong, {Wing H.} and Lynda Chin and Ligon, {Keith L.} and DePinho, {Ronald A.}",

note = "Funding Information: J.-h.P. is Damon Runyon Fellow was supported by the Damon Runyon Cancer Research Foundation (DRG 1900-06). Grant support includes the Claudia Adam Barr Foundation (J.-h.P.), ACS fellowship (F.M.), ABTA fellowship (H.Y.), Ellison Medical Foundation (R.A.D.), and 5P01CA95616 (R.A.D., K.L.L., L.C.). R.A.D. is an American Cancer Society Research Professor and supported by the Robert A. and Renee E. Belfer Foundation Institute for Applied Cancer Science. We thank D. Pellman and S. Yoshida for the deconvolution microscope use and advice, R. Maser for MSCV-puro-v5 gateway vector, W. Hahn for shRNA constructs, and J. Ling for technical assistance. ",

year = "2009",

month = nov,

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doi = "10.1016/j.stem.2009.09.013",

language = "English (US)",

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AU - Paik, Ji hye

AU - Ding, Zhihu

AU - Narurkar, Rujuta

AU - Ramkissoon, Shakti

AU - Muller, Florian

AU - Kamoun, Walid S.

AU - Chae, Sung Suk

AU - Zheng, Hongwu

AU - Ying, Haoqiang

AU - Mahoney, Jed

AU - Hiller, David

AU - Jiang, Shan

AU - Protopopov, Alexei

AU - Wong, Wing H.

AU - Chin, Lynda

AU - Ligon, Keith L.

AU - DePinho, Ronald A.

N1 - Funding Information: J.-h.P. is Damon Runyon Fellow was supported by the Damon Runyon Cancer Research Foundation (DRG 1900-06). Grant support includes the Claudia Adam Barr Foundation (J.-h.P.), ACS fellowship (F.M.), ABTA fellowship (H.Y.), Ellison Medical Foundation (R.A.D.), and 5P01CA95616 (R.A.D., K.L.L., L.C.). R.A.D. is an American Cancer Society Research Professor and supported by the Robert A. and Renee E. Belfer Foundation Institute for Applied Cancer Science. We thank D. Pellman and S. Yoshida for the deconvolution microscope use and advice, R. Maser for MSCV-puro-v5 gateway vector, W. Hahn for shRNA constructs, and J. Ling for technical assistance.

PY - 2009/11/6

Y1 - 2009/11/6

N2 - The PI3K-AKT-FoxO pathway is integral to lifespan regulation in lower organisms and essential for the stability of long-lived cells in mammals. Here, we report the impact of combined FoxO1, 3, and 4 deficiencies on mammalian brain physiology with a particular emphasis on the study of the neural stem/progenitor cell (NSC) pool. We show that the FoxO family plays a prominent role in NSC proliferation and renewal. FoxO-deficient mice show initial increased brain size and proliferation of neural progenitor cells during early postnatal life, followed by precocious significant decline in the NSC pool and accompanying neurogenesis in adult brains. Mechanistically, integrated transcriptomic, promoter, and functional analyses of FoxO-deficient NSC cultures identified direct gene targets with known links to the regulation of human brain size and the control of cellular proliferation, differentiation, and oxidative defense. Thus, the FoxO family coordinately regulates diverse genes and pathways to govern key aspects of NSC homeostasis in the mammalian brain.

AB - The PI3K-AKT-FoxO pathway is integral to lifespan regulation in lower organisms and essential for the stability of long-lived cells in mammals. Here, we report the impact of combined FoxO1, 3, and 4 deficiencies on mammalian brain physiology with a particular emphasis on the study of the neural stem/progenitor cell (NSC) pool. We show that the FoxO family plays a prominent role in NSC proliferation and renewal. FoxO-deficient mice show initial increased brain size and proliferation of neural progenitor cells during early postnatal life, followed by precocious significant decline in the NSC pool and accompanying neurogenesis in adult brains. Mechanistically, integrated transcriptomic, promoter, and functional analyses of FoxO-deficient NSC cultures identified direct gene targets with known links to the regulation of human brain size and the control of cellular proliferation, differentiation, and oxidative defense. Thus, the FoxO family coordinately regulates diverse genes and pathways to govern key aspects of NSC homeostasis in the mammalian brain.

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JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 5

ER -

FoxOs Cooperatively Regulate Diverse Pathways Governing Neural Stem Cell Homeostasis

Abstract

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