Fbxw7-dependent degradation of notch is required for control of "Stemness" and neuronal-glial differentiation in neural stem cells

Akinobu Matsumoto, Ichiro Onoyama, Takehiko Sunabori, Ryoichiro Kageyama, Hideyuki Okano, Keiichi I. Nakayama

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Control of the growth and differentiation of neural stem cells is fundamental to brain development and is largely dependent on the Notch signaling pathway. The mechanism by which the activity of Notch is regulated during brain development has remained unclear, however. Fbxw7 (also known as Fbw7, SEL- 10, hCdc4, or hAgo) is the F-box protein subunit of an Skp1- Cul1-F-box protein (SCF)-type ubiquitin ligase complex that plays a central role in the degradation of Notch family members. We now show that mice with brain-specific deletion of Fbxw7 (Nestin-Cre/Fbxw7F/F mice) die shortly after birth with morphological abnormalities of the brain and the absence of suckling behavior. The maintenance of neural stem cells was sustained in association with the accumulation of Notch1 and Notch3, as well as up-regulation of Notch target genes in the mutant mice. Astrogenesis was also enhanced in the mutant mice in vivo, and the differentiation of neural progenitor cells was skewed toward astrocytes rather than neurons in vitro, with the latter effect being reversed by treatment of the cells with a pharmacological inhibitor of the Notch signaling pathway. Our results thus implicate Fbxw7 as a key regulator of the maintenance and differentiation of neural stem cells in the brain.

Original languageEnglish
Pages (from-to)13754-13764
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number15
DOIs
Publication statusPublished - 2011 Apr 15

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Neural Stem Cells
Stem cells
Neuroglia
Brain
Degradation
F-Box Proteins
Maintenance
Nestin
Protein Subunits
Ligases
Ubiquitin
Astrocytes
Neurons
Up-Regulation
Stem Cells
Genes
Cells
Association reactions
Parturition
Pharmacology

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Fbxw7-dependent degradation of notch is required for control of "Stemness" and neuronal-glial differentiation in neural stem cells. / Matsumoto, Akinobu; Onoyama, Ichiro; Sunabori, Takehiko; Kageyama, Ryoichiro; Okano, Hideyuki; Nakayama, Keiichi I.

In: Journal of Biological Chemistry, Vol. 286, No. 15, 15.04.2011, p. 13754-13764.

Research output: Contribution to journalArticle

Matsumoto, Akinobu ; Onoyama, Ichiro ; Sunabori, Takehiko ; Kageyama, Ryoichiro ; Okano, Hideyuki ; Nakayama, Keiichi I. / Fbxw7-dependent degradation of notch is required for control of "Stemness" and neuronal-glial differentiation in neural stem cells. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 15. pp. 13754-13764.
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