Accumulation of mutations and somatic selection in aging neural stem/progenitor cells

Kimberly J. Bailey, Alexander Y. Maslov, Steven C. Pruitt

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Genomic instability within somatic stem cells may lead to the accumulation of mutations and contribute to cancer or other age-related phenotypes. However, determining the frequency of mutations that differ among individual stem cells is difficult from whole tissue samples because each event is dilluted in the total population of both stem cells and differentiated tissue. Here the ability to expand neural stem/progenitor cells clonally permitted measurement of genomic alterations derived from a single initial cell. C57BI/6 × DBA/2 hybrid mice were used and PCR analysis with strain-specific primers was performed to detect loss of heterozygosity on nine different chromosomes for each neurosphere. The frequency with which changes occurred in neurospheres derived from 2-month- and 2-year-old mice was compared. In 15 neurospheres derived from young animals both parental chromosomes were present for all nine chromosome pairs. In contrast, 16/17 neurospheres from old animals demonstrated loss of heterozygosity (LOH) on one or more chromosomes and seven exhibited a complete deletion of at least one chromosomal region. For chromosomes 9 and 19 there is a significant bias in the allele is retained in 6/6 neurospheres exhibiting LOH. These data suggest that aging leads to a substantial mutational load within the neural stem cell compartment which can be expected to affect the normal function of these cells. Furthermore, the retention of specific alleles for chromosomes 9 and 19 suggests that a subset of mutational events lead to an allele-specific survival advantage within the neural stem cell compartment.

Original languageEnglish (US)
Pages (from-to)391-397
Number of pages7
JournalAging cell
Volume3
Issue number6
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

Keywords

  • Aging
  • Central nervous system
  • DNA damage
  • Genetics
  • Molecular biology of aging
  • Mutagenesis
  • Neural stem cells
  • Neurogenesis

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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