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/Fbxw7(F/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.
Highlights
Notch regulates the expression of a cascade of transcription factors belonging to the basic helix-loop-helix family [1, 9, 10]
Accumulation of Notch in the Fbxw7-deficient Brain—Given that neurogenesis is regulated by the Notch signaling pathway, we examined the expression of Notch proteins and their downstream targets in the brain of the mutant animals
The products of the proneural genes Mash1 and Ngn2 activate the transcription of Dll1, which encodes a ligand of Notch (Delta-like 1), and the signaling triggered by the Dll1-Notch interaction suppresses the expression of the proneural genes via activation of Hes1 expression and thereby prevents neuronal differentiation [42]
Summary
F-box- and WD repeat domain-containing protein 7; MBP, myelin basic protein; GFAP, glial fibrillary acidic protein; ARBP, acidic ribosomal phosphoprotein; BLBP, brain lipid-binding protein; E18.5, embryonic day 18.5; P0.5, postnatal day 0.5; DAPT, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester; pHH3, phosphorylated histone 3. Role of Fbxw in Neural Stem Cells morphological abnormalities in the brain and the apparent accumulation of Notch. The growth of neural stem cells was enhanced, and the differentiation of these cells was skewed toward astrocytes. We propose that Fbxw plays a pivotal role in regulation of the abundance of Notch proteins by ubiquitin-dependent degradation in neural stem cells and thereby contributes to generation of the proper number and ratio of neurons and glial cells, a process that is essential for normal brain development
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