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DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM

L Carlessi1, L De Filippis, D Lecis

  • 1Department of Experimental Oncology, Fondazione IRCSS Istituto Nazionale Tumori, Milan, Italy.

Cell Death and Differentiation
|February 21, 2009
PubMed

Insights

Ataxia-telangiectasia (A-T) involves ATM kinase defects. This study used neural stem cells to show ATM ablation impacts neurogenesis and DNA damage response, revealing its role in neurodegeneration.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Ataxia-telangiectasia (A-T) is a neurodegenerative disorder linked to ATM kinase dysfunction.
  • The DNA-damage response (DDR) pathway is crucial for maintaining genomic stability and cellular health.
  • Understanding ATM's role in neural development and response to DNA damage is critical.

Purpose of the Study:

  • To investigate the role of ATM kinase in neural stem cell differentiation and DNA damage response.
  • To assess the impact of ATM ablation on neurogenesis and cellular susceptibility to stress.
  • To evaluate the utility of immortalized human neural stem cells (ihNSCs) as a model for studying A-T and DDR genes.

Main Methods:

  • Utilized an immortalized human neural stem-cell line (ihNSC) for in vitro differentiation studies.
  • Employed shRNA interference (shATM) to deplete ATM expression in ihNSCs.
  • Assessed ATM-dependent responses to ionizing radiation (IR) and differentiation-associated apoptosis.
  • Analyzed cell growth, self-renewal, genomic stability, and differentiation into neurons, oligodendrocytes, and astrocytes.

Main Results:

  • ihNSC differentiation involved dynamic changes in DDR proteins (ATM, DNA-PK, ATR, Chk1, p53).
  • ATM-deficient cells showed attenuated differentiation-associated apoptosis and reduced response to IR.
  • ATM depletion did not affect ihNSC growth, self-renewal, or genomic stability.
  • shATM cells produced normal neurons but fewer, more oxidative stress-susceptible oligodendrocytes.

Conclusions:

  • ihNSCs serve as a valuable in vitro model for studying ATM function in neurogenesis and neurodegeneration.
  • ATM plays a specific role in oligodendrocyte differentiation and survival.
  • This model system can be used to explore the broader roles of DDR genes in neurological disorders.

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