FoxO3 Regulates Neural Stem Cell Homeostasis

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2009 Nov 10

PMID 19896443

Citations 322

Authors

Valerie M Renault

Victoria A Rafalski

Alex A Morgan

Dervis A M Salih

Jamie O Brett

Ashley E Webb

Saul A Villeda

Pramod U Thekkat

Camille Guillerey

Nicholas C Denko

Theo D Palmer

Atul J Butte

Anne Brunet

Affiliations

Soon will be listed here.

Abstract

In the nervous system, neural stem cells (NSCs) are necessary for the generation of new neurons and for cognitive function. Here we show that FoxO3, a member of a transcription factor family known to extend lifespan in invertebrates, regulates the NSC pool. We find that adult FoxO3(-/-) mice have fewer NSCs in vivo than wild-type counterparts. NSCs isolated from adult FoxO3(-/-) mice have decreased self-renewal and an impaired ability to generate different neural lineages. Identification of the FoxO3-dependent gene expression profile in NSCs suggests that FoxO3 regulates the NSC pool by inducing a program of genes that preserves quiescence, prevents premature differentiation, and controls oxygen metabolism. The ability of FoxO3 to prevent the premature depletion of NSCs might have important implications for counteracting brain aging in long-lived species.

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References

Paik J, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z . FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell. 2007; 128(2):309-23. PMC: 1855089. DOI: 10.1016/j.cell.2006.12.029. View

Sun L, Evans M, Hsieh J, Panici J, Bartke A . Increased neurogenesis in dentate gyrus of long-lived Ames dwarf mice. Endocrinology. 2004; 146(3):1138-44. DOI: 10.1210/en.2004-1115. View

Tropepe V, Craig C, Morshead C, van der Kooy D . Transforming growth factor-alpha null and senescent mice show decreased neural progenitor cell proliferation in the forebrain subependyma. J Neurosci. 1997; 17(20):7850-9. PMC: 6793925. View

Flachsbart F, Caliebe A, Kleindorp R, Blanche H, von Eller-Eberstein H, Nikolaus S . Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci U S A. 2009; 106(8):2700-5. PMC: 2650329. DOI: 10.1073/pnas.0809594106. View

Paik J, Ding Z, Narurkar R, Ramkissoon S, Muller F, Kamoun W . FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell. 2009; 5(5):540-53. PMC: 3285492. DOI: 10.1016/j.stem.2009.09.013. View

Willcox B, Donlon T, He Q, Chen R, Grove J, Yano K . FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci U S A. 2008; 105(37):13987-92. PMC: 2544566. DOI: 10.1073/pnas.0801030105. View

Emerling B, Weinberg F, Liu J, Mak T, Chandel N . PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor 3a (FOXO3a). Proc Natl Acad Sci U S A. 2008; 105(7):2622-7. PMC: 2268186. DOI: 10.1073/pnas.0706790105. View

Miyamoto K, Araki K, Naka K, Arai F, Takubo K, Yamazaki S . Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell. 2008; 1(1):101-112. DOI: 10.1016/j.stem.2007.02.001. View

Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban P . Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat Genet. 1999; 23(1):99-103. DOI: 10.1038/12703. View

10.

Fasano C, Dimos J, Ivanova N, Lowry N, Lemischka I, Temple S . shRNA knockdown of Bmi-1 reveals a critical role for p21-Rb pathway in NSC self-renewal during development. Cell Stem Cell. 2008; 1(1):87-99. DOI: 10.1016/j.stem.2007.04.001. View

11.

Sinor A, Lillien L . Akt-1 expression level regulates CNS precursors. J Neurosci. 2004; 24(39):8531-41. PMC: 6729906. DOI: 10.1523/JNEUROSCI.1470-04.2004. View

12.

Kempermann G, Kuhn H, Gage F . Experience-induced neurogenesis in the senescent dentate gyrus. J Neurosci. 1998; 18(9):3206-12. PMC: 6792643. View

13.

Studer L, Csete M, Lee S, Kabbani N, Walikonis J, Wold B . Enhanced proliferation, survival, and dopaminergic differentiation of CNS precursors in lowered oxygen. J Neurosci. 2000; 20(19):7377-83. PMC: 6772777. View

14.

Shen Q, Wang Y, Kokovay E, Lin G, Chuang S, Goderie S . Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell. 2008; 3(3):289-300. PMC: 2747473. DOI: 10.1016/j.stem.2008.07.026. View

15.

Tavazoie M, van der Veken L, Silva-Vargas V, Louissaint M, Colonna L, Zaidi B . A specialized vascular niche for adult neural stem cells. Cell Stem Cell. 2008; 3(3):279-88. PMC: 6864413. DOI: 10.1016/j.stem.2008.07.025. View

16.

Molofsky A, Slutsky S, Joseph N, He S, Pardal R, Krishnamurthy J . Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature. 2006; 443(7110):448-52. PMC: 2586960. DOI: 10.1038/nature05091. View

17.

Li L, Liu F, Salmonsen R, Turner T, Litofsky N, Di Cristofano A . PTEN in neural precursor cells: regulation of migration, apoptosis, and proliferation. Mol Cell Neurosci. 2002; 20(1):21-9. DOI: 10.1006/mcne.2002.1115. View

18.

Bakker W, Harris I, Mak T . FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2. Mol Cell. 2007; 28(6):941-53. DOI: 10.1016/j.molcel.2007.10.035. View

19.

Keith B, Simon M . Hypoxia-inducible factors, stem cells, and cancer. Cell. 2007; 129(3):465-72. PMC: 3150586. DOI: 10.1016/j.cell.2007.04.019. View

20.

Imayoshi I, Sakamoto M, Ohtsuka T, Takao K, Miyakawa T, Yamaguchi M . Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat Neurosci. 2008; 11(10):1153-61. DOI: 10.1038/nn.2185. View