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Published on: January 12, 2015
Requirement for DNA ligase IV during embryonic neuronal development
Susanne A Gatz1, Limei Ju, Ralph Gruber
1Development and Stem Cell Institute, Key Laboratory of Ministry of Education, Department of Paediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.
Summary
DNA double-strand breaks (DSBs) trigger apoptosis in embryonic brain regions. The ventricular/subventricular zone (VZ/SVZ) is sensitive to acute breaks, while the intermediate zone (IZ) is sensitive to persistent breaks, impacting brain development.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The embryonic ventricular and subventricular zones (VZ/SVZ) are critical for neurogenesis, housing neural stem and progenitor cells.
- The intermediate zone (IZ) comprises differentiated, non-proliferating cells.
- The VZ/SVZ exhibits hypersensitivity to radiation-induced apoptosis, while DNA repair protein deficiencies cause apoptosis in the IZ.
Purpose of the Study:
- To investigate the mechanistic basis for distinct DNA double-strand break (DSB) sensitivities in the embryonic VZ/SVZ and IZ.
- To analyze DNA damage responses in the embryonic and adult brain using a viable DNA ligase IV (LigIV) mutant mouse model.
Main Methods:
- Combined analysis of DNA breakage, apoptosis, and cell-cycle checkpoint control in tissues.
- Utilized a LigIV (Lig4(Y288C)) mouse model to study DNA damage responses.
- Assessed ATM-dependent and independent apoptotic pathways.
Main Results:
- Apoptosis in both VZ/SVZ and IZ is induced by low numbers of DSBs.
- VZ/SVZ exhibits high sensitivity due to ATM-dependent and independent apoptosis.
- IZ shows hypersensitivity to persistent DSBs, with efficient Non-homologous end-joining (NHEJ) in both compartments.
- High endogenous DNA breakage in VZ/SVZ correlates with proliferation and leads to damaged cells transiting to the IZ.
Conclusions:
- A novel model proposes that microcephaly in LIG4 syndrome results from persistent DSBs in the IZ, originating from high endogenous breakage in the VZ/SVZ.
- The VZ/SVZ is highly sensitive to acute radiation-induced DSBs, whereas the IZ is sensitive to persistent DSBs.
