Linked Life Data

20484632

Source:http://linkedlifedata.com/resource/pubmed/id/20484632

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
20
pubmed:dateCreated
2010-5-20
pubmed:abstractText
The vast majority of pedigrees with familial Alzheimer's disease (FAD) are caused by inheritance of mutations in the PSEN1 1 gene. While genetic ablation studies have revealed a role for presenilin 1 (PS1) in embryonic neurogenesis, little information has emerged regarding the potential effects of FAD-linked PS1 variants on proliferation, self-renewal and differentiation, key events that control cell fate commitment of adult brain neural progenitors (NPCs). We used adult brain subventricular zone (SVZ)-derived NPC cultures transduced with recombinant lentivirus as a means to investigate the effects of various PS1 mutants on self-renewal and differentiation properties. We now show that viral expression of several PS1 mutants in NPCs leads to impaired self-renewal and altered differentiation toward neuronal lineage, in vitro. In line with these observations, diminished constitutive proliferation and steady-state SVZ progenitor pool size was observed in vivo in transgenic mice expressing the PS1DeltaE9 variant. Moreover, NPC cultures established from the SVZ of adult mice expressing PS1DeltaE9 exhibit reduced self-renewal capacity and premature exit toward neuronal fates. To these findings, we show that both the levels of endogenous Notch/CBF-1-transcriptional activity and transcripts encoding Notch target genes are diminished in SVZ NPCs expressing PS1DeltaE9. The deficits in self-renewal and multipotency are restored by expression of Notch1-ICD or a downstream target of the Notch pathway, Hes1. Hence, we argue that a partial reduction in PS-dependent gamma-secretase processing of the Notch, at least in part, accounts for the impairments observed in SVZ NPCs expressing the FAD-linked PS1DeltaE9 variant.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1529-2401
pubmed:author
pubmed:issnType
Electronic
pubmed:day
19
pubmed:volume
30
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
6903-15
pubmed:dateRevised
2011-9-26
pubmed:meshHeading
pubmed-meshheading:20484632-Adult Stem Cells, pubmed-meshheading:20484632-Analysis of Variance, pubmed-meshheading:20484632-Animals, pubmed-meshheading:20484632-Bromodeoxyuridine, pubmed-meshheading:20484632-Cell Differentiation, pubmed-meshheading:20484632-Cells, Cultured, pubmed-meshheading:20484632-Humans, pubmed-meshheading:20484632-Lateral Ventricles, pubmed-meshheading:20484632-Mice, pubmed-meshheading:20484632-Mice, Inbred C57BL, pubmed-meshheading:20484632-Mice, Transgenic, pubmed-meshheading:20484632-Mutation, pubmed-meshheading:20484632-Nerve Tissue Proteins, pubmed-meshheading:20484632-Neurons, pubmed-meshheading:20484632-Presenilin-1, pubmed-meshheading:20484632-Proto-Oncogene Proteins, pubmed-meshheading:20484632-Receptors, Notch, pubmed-meshheading:20484632-Signal Transduction, pubmed-meshheading:20484632-Transfection
pubmed:year
2010
pubmed:articleTitle
Presenilin 1 mutants impair the self-renewal and differentiation of adult murine subventricular zone-neuronal progenitors via cell-autonomous mechanisms involving notch signaling.
pubmed:affiliation
Department of Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural