Involvement of Atm and Trp53 in neural cell loss due to Terf2 inactivation during mouse brain development
Jusik Kim1,2, Inseo Choi1,2, Youngsoo Lee3,4
1Genomic Instability Research Center, School of Medicine, Ajou University, Suwon, 16499, Republic of Korea.
Abstract:
Maintenance of genomic integrity is one of the critical features for proper neurodevelopment and inhibition of neurological diseases. The signals from both ATM and ATR to TP53 are well-known mechanisms to remove neural cells with DNA damage during neurogenesis. Here we examined the involvement of Atm and Atr in genomic instability due to Terf2 inactivation during mouse brain development. Selective inactivation of Terf2 in neural progenitors induced apoptosis, resulting in a complete loss of the brain structure. This neural loss was rescued partially in both Atm and Trp53 deficiency, but not in an Atr-deficient background in the mouse. Atm inactivation resulted in incomplete brain structures, whereas p53 deficiency led to the formation of multinucleated giant neural cells and the disruption of the brain structure. These giant neural cells disappeared in Lig4 deficiency. These data demonstrate ATM and TP53 are important for the maintenance of telomere homeostasis and the surveillance of telomere dysfunction during neurogenesis.
Insights
The study reveals that ATM and TP53 are crucial for maintaining genomic stability during mouse brain development after TERF2 inactivation. Their absence leads to abnormal neural cell formation and disrupted brain structures.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Genomic integrity is vital for neurodevelopment and preventing neurological diseases.
- ATM, ATR, and TP53 pathways are known to manage DNA damage in neural cells during neurogenesis.
Purpose of the Study:
- To investigate the roles of ATM and ATR in genomic instability caused by TERF2 inactivation during mouse brain development.
- To understand the specific contributions of ATM and TP53 to neural cell survival and brain structure maintenance.
Main Methods:
- Selective inactivation of the TERF2 gene in neural progenitors in mice.
- Analysis of brain development and cell survival in Atm, Atr, Trp53, and Lig4 deficient backgrounds.
- Assessment of genomic instability and telomere homeostasis.
Main Results:
- TERF2 inactivation in neural progenitors caused severe brain structure loss via apoptosis.
- This loss was partially rescued by Atm or Trp53 deficiency, but not Atr deficiency.
- Atm deficiency led to incomplete brain structures; Trp53 deficiency resulted in multinucleated giant neural cells, which were absent in Lig4 deficiency.
Conclusions:
- ATM and TP53 are essential for maintaining telomere homeostasis and monitoring telomere dysfunction during neurogenesis.
- The findings highlight the critical roles of ATM and TP53 in ensuring genomic stability for proper brain development.
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