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Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system
K H Herzog1, M J Chong, M Kapsetaki
1Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38101, USA.
Abstract:
Ataxia telangiectasia (AT) is characterized by progressive neurodegeneration that results from mutation of the ATM gene. However, neither the normal function of ATM in the nervous system nor the biological basis of the degeneration in AT is known. Resistance to apoptosis in the developing central nervous system (CNS) of Atm-/- mice was observed after ionizing radiation. This lack of death occurred in diverse regions of the CNS, including the cerebellum, which is markedly affected in AT. In wild-type, but not Atm-/- mice, up-regulation of p53 coincided with cell death, suggesting that Atm-dependent apoptosis in the CNS is mediated by p53. Further, p53 null mice showed a similar lack of radiation-induced cell death in the developing nervous system. Atm may function at a developmental survival checkpoint that serves to eliminate neurons with excessive DNA damage.
Insights
Ataxia telangiectasia (AT) involves neurodegeneration due to ATM gene mutations. Research shows ATM regulates apoptosis in the developing nervous system, preventing neuron survival with DNA damage.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Ataxia telangiectasia (AT) is a severe neurodegenerative disorder caused by mutations in the ATM gene.
- The precise function of the ATM gene in the nervous system and the mechanisms underlying AT-related neurodegeneration remain largely unknown.
- Apoptosis, or programmed cell death, plays a critical role in nervous system development and maintenance.
Purpose of the Study:
- To investigate the role of the ATM gene in regulating apoptosis within the developing central nervous system (CNS).
- To elucidate the biological basis of neurodegeneration observed in Ataxia telangiectasia.
Main Methods:
- Utilizing Atm-/- mice (lacking functional ATM gene) and wild-type controls.
- Administering ionizing radiation to assess cell death responses in the developing CNS.
- Analyzing the expression levels of p53, a key protein in DNA damage response and apoptosis pathways.
- Comparing radiation-induced cell death in Atm-/- mice, wild-type mice, and p53 null mice.
Main Results:
- Atm-/- mice exhibited resistance to radiation-induced apoptosis in various regions of the developing CNS, including the cerebellum.
- In wild-type mice, p53 levels increased concurrently with cell death following irradiation, a phenomenon not observed in Atm-/- mice.
- p53 null mice also displayed a lack of radiation-induced cell death in the developing nervous system, similar to Atm-/- mice.
- These findings suggest that ATM-dependent apoptosis in the CNS is mediated by the p53 pathway.
Conclusions:
- The ATM gene is crucial for initiating apoptosis in response to DNA damage in the developing CNS.
- ATM likely functions at a developmental checkpoint to eliminate neurons with excessive DNA damage, preventing neurodegeneration.
- Dysfunction of ATM, as seen in Ataxia telangiectasia, disrupts this checkpoint, potentially leading to the accumulation of damaged neurons and subsequent neurodegeneration.