Home LiteratureArticle Details
PMID: 18086919 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Cdk2 is critical for proliferation and self-renewal of neural progenitor cells in the adult subventricular zone.

The Journal of cell biology ·Vol. 179 ·No. 6 ·2007-12-17 ·Pages 1231-45

Jablonska B, Aguirre A, Vandenbosch R, Belachew S, Berthet C, Kaldis P, Gallo V

Abstract

We investigated the function of cyclin-dependent kinase 2 (Cdk2) in neural progenitor cells during postnatal development. Chondroitin sulfate proteoglycan (NG2)-expressing progenitor cells of the subventricular zone (SVZ) show no significant difference in density and proliferation between Cdk2(-/-) and wild-type mice at perinatal ages and are reduced only in adult Cdk2(-/-) mice. Adult Cdk2(-/-) SVZ cells in culture display decreased self-renewal capacity and enhanced differentiation. Compensatory mechanisms in perinatal Cdk2(-/-) SVZ cells, which persist until postnatal day 15, involve increased Cdk4 expression that results in retinoblastoma protein inactivation. A subsequent decline in Cdk4 activity to wild-type levels in postnatal day 28 Cdk2(-/-) cells coincides with lower NG2+ proliferation and self-renewal capacity similar to adult levels. Cdk4 silencing in perinatal Cdk2(-/-) SVZ cells abolishes Cdk4 up-regulation and reduces cell proliferation and self- renewal to adult levels. Conversely, Cdk4 overexpression in adult SVZ cells restores proliferative capacity to wild-type levels. Thus, although Cdk2 is functionally redundant in perinatal SVZ, it is important for adult progenitor cell proliferation and self-renewal through age-dependent regulation of Cdk4.

MeSH Terms
Animals Cell Cycle Proteins/genetics,metabolism Cell Lineage Cell Proliferation Cerebral Ventricles/cytology,metabolism Chondroitin Sulfate Proteoglycans/metabolism Cyclin-Dependent Kinase 2/physiology Cyclin-Dependent Kinase 4/physiology Gene Expression Regulation, Developmental Mice Neurons/cytology Stem Cells/cytology,metabolism
Chemicals
Cell Cycle Proteins Chondroitin Sulfate Proteoglycans Cdk2 protein, mouse Cdk4 protein, mouse Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase 4
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Jablonska Beata
Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA.
Aguirre Adan
Vandenbosch Renaud
Belachew Shibeshih
Berthet Cyril
Kaldis Philipp
Gallo Vittorio
References (54)
54 references, click to expand
  1. Inhibition of cyclin E-cyclin-dependent kinase 2 complex formation and activity is associated with cell cycle arrest and withdrawal in oligodendrocyte progenitor cells.
    J Neurosci. 2001 Feb 15;21(4):1274-82 PMID: 11160398
  2. Long-distance neuronal migration in the adult mammalian brain.
    Science. 1994 May 20;264(5162):1145-8 PMID: 8178174
  3. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo.
    Nat Neurosci. 2003 Jan;6(1):21-7 PMID: 12469128
  4. Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice.
    Nat Genet. 2003 Sep;35(1):25-31 PMID: 12923533
  5. Origin of oligodendrocytes in the subventricular zone of the adult brain.
    J Neurosci. 2006 Jul 26;26(30):7907-18 PMID: 16870736
  6. Loss of p27Kip1 function results in increased proliferative capacity of oligodendrocyte progenitors but unaltered timing of differentiation.
    Development. 1999 Sep;126(18):4027-37 PMID: 10457012
  7. Combined loss of Cdk2 and Cdk4 results in embryonic lethality and Rb hypophosphorylation.
    Dev Cell. 2006 May;10(5):563-73 PMID: 16678773
  8. In vivo clonal analyses reveal the properties of endogenous neural stem cell proliferation in the adult mammalian forebrain.
    Development. 1998 Jun;125(12):2251-61 PMID: 9584124
  9. Postnatal NG2 proteoglycan-expressing progenitor cells are intrinsically multipotent and generate functional neurons.
    J Cell Biol. 2003 Apr 14;161(1):169-86 PMID: 12682089
  10. Cyclin-dependent kinase-2 controls oligodendrocyte progenitor cell cycle progression and is downregulated in adult oligodendrocyte progenitors.
    J Neurosci. 2002 Oct 1;22(19):8553-62 PMID: 12351729
  11. p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex.
    Genes Dev. 2006 Jun 1;20(11):1511-24 PMID: 16705040
  12. Receptor tyrosine kinase ErbB4 modulates neuroblast migration and placement in the adult forebrain.
    Nat Neurosci. 2004 Dec;7(12):1319-28 PMID: 15543145
  13. Cdk2 knockout mice are viable.
    Curr Biol. 2003 Oct 14;13(20):1775-85 PMID: 14561402
  14. Adult neurogenesis and functional plasticity in neuronal circuits.
    Nat Rev Neurosci. 2006 Mar;7(3):179-93 PMID: 16495940
  15. Neurotransmitter receptor activation triggers p27(Kip1 )and p21(CIP1) accumulation and G1 cell cycle arrest in oligodendrocyte progenitors.
    Development. 1999 Feb;126(5):1077-90 PMID: 9927607
  16. Biphasic effects of exogenous VEGF on VEGF expression of adult neural progenitors.
    Neurosci Lett. 2006 Jan 30;393(2-3):97-101 PMID: 16269210
  17. Control of pRB phosphorylation.
    Curr Opin Genet Dev. 1998 Feb;8(1):21-7 PMID: 9529601
  18. Retinoblastoma tumor suppressor: where cancer meets the cell cycle.
    Exp Biol Med (Maywood). 2006 Jul;231(7):1271-81 PMID: 16816134
  19. E2F-induced S phase requires cyclin E.
    Genes Dev. 1996 Oct 1;10(19):2505-13 PMID: 8843201
  20. Distinct roles for cyclin-dependent kinases in cell cycle control.
    Science. 1993 Dec 24;262(5142):2050-4 PMID: 8266103
  21. EphrinB3 regulates cell proliferation and survival in adult neurogenesis.
    Mol Cell Neurosci. 2006 Apr;31(4):713-22 PMID: 16483793
  22. A pathway regulated by cell cycle inhibitor p27Kip1 and checkpoint inhibitor Smad3 is involved in the induction of T cell tolerance.
    Nat Immunol. 2006 Nov;7(11):1157-65 PMID: 17013388
  23. Mash1 specifies neurons and oligodendrocytes in the postnatal brain.
    EMBO J. 2004 Nov 10;23(22):4495-505 PMID: 15496983
  24. Cell cycle and cell fate in the nervous system.
    Curr Opin Neurobiol. 2001 Feb;11(1):66-73 PMID: 11179874
  25. Cell cycle parameters and patterns of nuclear movement in the neocortical proliferative zone of the fetal mouse.
    J Neurosci. 1993 Feb;13(2):820-33 PMID: 8426239
  26. Regulation of neural progenitor proliferation and survival by beta1 integrins.
    J Cell Sci. 2005 Jun 15;118(Pt 12):2589-99 PMID: 15928047
  27. Cyclin/Cdk-dependent initiation of DNA replication in a human cell-free system.
    Cell. 1997 Jan 10;88(1):109-19 PMID: 9019396
  28. Cell output, cell cycle duration and neuronal specification: a model of integrated mechanisms of the neocortical proliferative process.
    Cereb Cortex. 2003 Jun;13(6):592-8 PMID: 12764033
  29. p27(Kip1) regulates cell cycle withdrawal of late multipotent progenitor cells in the mammalian retina.
    Dev Biol. 2000 Mar 15;219(2):299-314 PMID: 10694424
  30. Cell cycle regulators and hematopoiesis.
    Oncogene. 2002 May 13;21(21):3403-13 PMID: 12032778
  31. Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone.
    Neuron. 1993 Jul;11(1):173-89 PMID: 8338665
  32. Overexpression of the epidermal growth factor receptor confers migratory properties to nonmigratory postnatal neural progenitors.
    J Neurosci. 2005 Nov 30;25(48):11092-106 PMID: 16319309
  33. Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone.
    Nat Neurosci. 2000 Nov;3(11):1091-7 PMID: 11036265
  34. Regulation of the retinoblastoma protein-related p107 by G1 cyclin complexes.
    Genes Dev. 1995 Jun 1;9(11):1340-53 PMID: 7797074
  35. Expression of INK4 inhibitors of cyclin D-dependent kinases during mouse brain development.
    Cell Growth Differ. 1997 Nov;8(11):1139-50 PMID: 9372237
  36. p21cip1 is required for the differentiation of oligodendrocytes independently of cell cycle withdrawal.
    EMBO Rep. 2001 Jan;2(1):27-34 PMID: 11252720
  37. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells.
    Science. 2004 May 28;304(5675):1338-40 PMID: 15060285
  38. Postnatal neurogenesis and gliogenesis in the olfactory bulb from NG2-expressing progenitors of the subventricular zone.
    J Neurosci. 2004 Nov 17;24(46):10530-41 PMID: 15548668
  39. Impaired adult neurogenesis in mice lacking the transcription factor E2F1.
    Mol Cell Neurosci. 2002 Oct;21(2):312-23 PMID: 12401450
  40. New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment?
    Trends Cell Biol. 2003 Feb;13(2):65-70 PMID: 12559756
  41. New functional activities for the p21 family of CDK inhibitors.
    Genes Dev. 1997 Apr 1;11(7):847-62 PMID: 9106657
  42. NG2-expressing cells in the subventricular zone are type C-like cells and contribute to interneuron generation in the postnatal hippocampus.
    J Cell Biol. 2004 May 24;165(4):575-89 PMID: 15159421
  43. Intrinsic and extrinsic regulation of the proliferation and differentiation of cells in the rodent rostral migratory stream.
    J Neurosci Res. 2002 Sep 15;69(6):795-802 PMID: 12205673
  44. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation.
    Nature. 2003 Oct 30;425(6961):962-7 PMID: 14574365
  45. Lack of the cell-cycle inhibitor p27Kip1 results in selective increase of transit-amplifying cells for adult neurogenesis.
    J Neurosci. 2002 Mar 15;22(6):2255-64 PMID: 11896165
  46. Cyclin-dependent kinases: engines, clocks, and microprocessors.
    Annu Rev Cell Dev Biol. 1997;13:261-91 PMID: 9442875
  47. Cell cycle length of olfactory bulb neuronal progenitors in the rostral migratory stream.
    Dev Dyn. 1998 Oct;213(2):220-7 PMID: 9786422
  48. A role for Cdk2 kinase in negatively regulating DNA replication during S phase of the cell cycle.
    J Cell Biol. 1997 Apr 7;137(1):183-92 PMID: 9105046
  49. p27Kip1 alters the response of cells to mitogen and is part of a cell-intrinsic timer that arrests the cell cycle and initiates differentiation.
    Curr Biol. 1998 Apr 9;8(8):431-40 PMID: 9550698
  50. The role of neuregulin-ErbB4 interactions on the proliferation and organization of cells in the subventricular zone.
    Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1930-5 PMID: 16446434
  51. Proliferation of cancer cells despite CDK2 inhibition.
    Cancer Cell. 2003 Mar;3(3):233-45 PMID: 12676582
  52. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing.
    Nature. 2006 Sep 28;443(7110):448-52 PMID: 16957738
  53. The expression pattern of the cell cycle inhibitor p19(INK4d) by progenitor cells of the rat embryonic telencephalon and neonatal anterior subventricular zone.
    J Neurosci. 2001 May 1;21(9):3092-103 PMID: 11312294
  54. NG2-expressing cells in the central nervous system: are they oligodendroglial progenitors?
    J Neurosci Res. 2000 Sep 1;61(5):471-9 PMID: 10956416
Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
1540-8140
DOI
10.1083/jcb.200702031
Published
2007-12-17
Pages
1231-45
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2140044
Subset
IM
Grants
NICHD NIH HHS · P30 HD040677 · United States
NINDS NIH HHS · R01 NS045702 · United States
NICHD NIH HHS · P30HD40677 · United States
NINDS NIH HHS · R01NS045702 · United States
External Links
PubMed source DOI: 10.1083/jcb.200702031 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2