Coordinated Control of Self-renewal and Differentiation of Neural Stem Cells by Myc and the P19ARF-p53 Pathway

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2008 Dec 31

PMID 19114593

Citations 38

Authors

Motoshi Nagao

Kenneth Campbell

Kevin Burns

Chia-Yi Kuan

Andreas Trumpp

Masato Nakafuku

Affiliations

Soon will be listed here.

Abstract

The modes of proliferation and differentiation of neural stem cells (NSCs) are coordinately controlled during development, but the underlying mechanisms remain largely unknown. In this study, we show that the protooncoprotein Myc and the tumor suppressor p19(ARF) regulate both NSC self-renewal and their neuronal and glial fate in a developmental stage-dependent manner. Early-stage NSCs have low p19(ARF) expression and retain a high self-renewal and neurogenic capacity, whereas late-stage NSCs with higher p19(ARF) expression possess a lower self-renewal capacity and predominantly generate glia. Overexpression of Myc or inactivation of p19(ARF) reverts the properties of late-stage NSCs to those of early-stage cells. Conversely, inactivation of Myc or forced p19(ARF) expression attenuates self-renewal and induces precocious gliogenesis through modulation of the responsiveness to gliogenic signals. These actions of p19(ARF) in NSCs are mainly mediated by p53. We propose that opposing actions of Myc and the p19(ARF)-p53 pathway have important functions in coordinated developmental control of self-renewal and cell fate choices in NSCs.

Citing Articles

Induction of -amplified neuroblastoma differentiation through NMYC suppression using PPAR-γ antagonist.

Nakao-Ise Y, Narita T, Miyamoto S, Watanabe M, Tanaka T, Sowa Y J Clin Biochem Nutr. 2023; 73(3):191-197.

PMID: 37970556 PMC: 10636585. DOI: 10.3164/jcbn.23-28.

Interstitial-fluid shear stresses induced by vertically oscillating head motion lower blood pressure in hypertensive rats and humans.

Murase S, Sakitani N, Maekawa T, Yoshino D, Takano K, Konno A Nat Biomed Eng. 2023; 7(11):1350-1373.

PMID: 37414976 PMC: 10651490. DOI: 10.1038/s41551-023-01061-x.

ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors.

Mainwaring O, Weishaupt H, Zhao M, Rosen G, Borgenvik A, Breinschmid L Nat Commun. 2023; 14(1):1221.

PMID: 36869047 PMC: 9984535. DOI: 10.1038/s41467-023-36847-9.

Cell Type-Specific Role of RNA Nuclease SMG6 in Neurogenesis.

Guerra G, May D, Kroll T, Koch P, Groth M, Wang Z Cells. 2021; 10(12).

PMID: 34943873 PMC: 8699217. DOI: 10.3390/cells10123365.

Proliferation rate and differentiation potential are independent during the transition from neurogenesis to gliogenesis in the mouse embryonic spinal cord.

Olivos-Cisneros L, Ramirez-Santos J, Gutierrez-Ospina G IBRO Neurosci Rep. 2021; 10:75-82.

PMID: 33842913 PMC: 8019975. DOI: 10.1016/j.ibneur.2020.11.004.

References

Zindy F, Knoepfler P, Xie S, Sherr C, Eisenman R, Roussel M . N-Myc and the cyclin-dependent kinase inhibitors p18Ink4c and p27Kip1 coordinately regulate cerebellar development. Proc Natl Acad Sci U S A. 2006; 103(31):11579-83. PMC: 1518798. DOI: 10.1073/pnas.0604727103. View

Berns K, Hijmans E, Bernards R . Repression of c-Myc responsive genes in cycling cells causes G1 arrest through reduction of cyclin E/CDK2 kinase activity. Oncogene. 1997; 15(11):1347-56. DOI: 10.1038/sj.onc.1201280. View

Suzuki A, Sekiya S, Buscher D, Izpisua Belmonte J, Taniguchi H . Tbx3 controls the fate of hepatic progenitor cells in liver development by suppressing p19ARF expression. Development. 2008; 135(9):1589-95. DOI: 10.1242/dev.016634. View

Nagao M, Sugimori M, Nakafuku M . Cross talk between notch and growth factor/cytokine signaling pathways in neural stem cells. Mol Cell Biol. 2007; 27(11):3982-94. PMC: 1900030. DOI: 10.1128/MCB.00170-07. View

Qian X, Shen Q, Goderie S, He W, Capela A, Davis A . Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron. 2000; 28(1):69-80. DOI: 10.1016/s0896-6273(00)00086-6. View

Zindy F, Eischen C, Randle D, Kamijo T, Cleveland J, Sherr C . Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev. 1998; 12(15):2424-33. PMC: 317045. DOI: 10.1101/gad.12.15.2424. View

Grandori C, Cowley S, James L, Eisenman R . The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu Rev Cell Dev Biol. 2000; 16:653-99. DOI: 10.1146/annurev.cellbio.16.1.653. View

Sage J, Miller A, Perez-Mancera P, Wysocki J, Jacks T . Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature. 2003; 424(6945):223-8. DOI: 10.1038/nature01764. View

Sugimori M, Nagao M, Bertrand N, Parras C, Guillemot F, Nakafuku M . Combinatorial actions of patterning and HLH transcription factors in the spatiotemporal control of neurogenesis and gliogenesis in the developing spinal cord. Development. 2007; 134(8):1617-29. DOI: 10.1242/dev.001255. View

10.

Sauvageot C, Stiles C . Molecular mechanisms controlling cortical gliogenesis. Curr Opin Neurobiol. 2002; 12(3):244-9. DOI: 10.1016/s0959-4388(02)00322-7. View

11.

Miller F, Gauthier A . Timing is everything: making neurons versus glia in the developing cortex. Neuron. 2007; 54(3):357-69. DOI: 10.1016/j.neuron.2007.04.019. View

12.

Davis A, Wims M, Spotts G, Hann S, Bradley A . A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice. Genes Dev. 1993; 7(4):671-82. DOI: 10.1101/gad.7.4.671. View

13.

Cleveland J, Sherr C . Antagonism of Myc functions by Arf. Cancer Cell. 2004; 6(4):309-11. DOI: 10.1016/j.ccr.2004.09.020. View

14.

Murphy M, Wilson A, Trumpp A . More than just proliferation: Myc function in stem cells. Trends Cell Biol. 2005; 15(3):128-37. DOI: 10.1016/j.tcb.2005.01.008. View

15.

Bruggeman S, Valk-Lingbeek M, van der Stoop P, Jacobs J, Kieboom K, Tanger E . Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice. Genes Dev. 2005; 19(12):1438-43. PMC: 1151660. DOI: 10.1101/gad.1299305. View

16.

Menard C, Hein P, Paquin A, Savelson A, Yang X, Lederfein D . An essential role for a MEK-C/EBP pathway during growth factor-regulated cortical neurogenesis. Neuron. 2002; 36(4):597-610. DOI: 10.1016/s0896-6273(02)01026-7. View

17.

Knoepfler P, Cheng P, Eisenman R . N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. Genes Dev. 2002; 16(20):2699-712. PMC: 187459. DOI: 10.1101/gad.1021202. View

18.

Shen Q, Wang Y, Dimos J, Fasano C, Phoenix T, Lemischka I . The timing of cortical neurogenesis is encoded within lineages of individual progenitor cells. Nat Neurosci. 2006; 9(6):743-51. DOI: 10.1038/nn1694. View

19.

Eilers M, Picard D, Yamamoto K, Bishop J . Chimaeras of myc oncoprotein and steroid receptors cause hormone-dependent transformation of cells. Nature. 1989; 340(6228):66-8. DOI: 10.1038/340066a0. View

20.

Bachoo R, Maher E, Ligon K, Sharpless N, Chan S, You M . Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell. 2002; 1(3):269-77. DOI: 10.1016/s1535-6108(02)00046-6. View