Related Experiment Video
Updated: Aug 4, 2026
Induction of Maternal Immune Activation in Mice at Mid-gestation Stage with Viral Mimic Poly(I:C)
Published on: March 25, 2016
Elevated DNA double strand breaks and apoptosis in the CNS of scid mutant mice
M C Vemuri1, E Schiller, J R Naegele
1Program in Neuroscience and Behavior, Department of Biology, Wesleyan University, Middletown, CT 06457, USA.
Abstract:
Genetic approaches have provided evidence that DNA end-joining problems serve an essential role in neuronal survival during development of mammalian embryos. In the present study, we tested whether the DNA repair enzyme, DNA dependent protein kinase, plays an important role in the survival of cerebral cortical neurons in mice. DNA-PK is comprised of a DNA-binding subunit called Ku and a catalytic subunit called DNA-PKcs. In mice with the scid mutation, DNA-PKcs is truncated near the kinase domain, which causes loss of kinase activity. We compared the spatial and temporal aspects of neuronal cell death in scid versus isogenic wild-type embryos and found a significant increase in dying cells in scid mice, as assessed by nuclear changes, DNA fragmentation and caspase-3 activity. Additional biochemical and immunocytochemical studies indicated that of several DNA repair enzymes investigated, only PARP was increased in scid mice, possibly in response to elevated DNA strand breaks.
Insights
DNA-dependent protein kinase (DNA-PK) is crucial for cerebral cortical neuron survival in developing mice. Impaired DNA-PK function in scid mice leads to increased neuronal cell death, highlighting its role in neurodevelopment.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- DNA end-joining is vital for neuronal survival during mammalian embryonic development.
- DNA-dependent protein kinase (DNA-PK) is a key DNA repair enzyme.
- The scid mutation in mice results in a truncated, inactive DNA-PK catalytic subunit (DNA-PKcs).
Purpose of the Study:
- To investigate the role of DNA-PK in the survival of cerebral cortical neurons in mice.
- To compare neuronal cell death in scid mutant mice and wild-type littermates.
Main Methods:
- Comparison of spatial and temporal aspects of neuronal cell death in scid and wild-type mouse embryos.
- Assessment of cell death using nuclear changes, DNA fragmentation, and caspase-3 activity.
- Biochemical and immunocytochemical analyses of DNA repair enzymes.
Main Results:
- A significant increase in dying cerebral cortical neurons was observed in scid mice compared to wild-type embryos.
- Evidence of increased neuronal cell death included nuclear abnormalities, DNA fragmentation, and elevated caspase-3 activity.
- Poly (ADP-ribose) polymerase (PARP) was the only DNA repair enzyme found to be upregulated in scid mice, suggesting a response to DNA strand breaks.
Conclusions:
- DNA-PK plays a critical role in the survival of cerebral cortical neurons during mouse embryonic development.
- The scid mutation, leading to defective DNA-PK, significantly exacerbates neuronal cell death.
- Elevated PARP levels in scid mice may indicate a compensatory response to increased DNA damage.
