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.
Highlights
Genomic instability resulting from DNA damage induced by either endogenous or exogenous insults could lead to defective neurodevelopment and neurological diseases (Lee et al 2016)
DNA damage or breaks could be visualized by immunostaining of phosphorylated H2AX (γ-H2AX) as foci formation in the nucleus. γ-H2AX foci were abundant in the giant nuclei of the Terf2Nes-Cre and (Terf2)/Trp53 double null cortices
The Terf2-null cortices in all different genetic backgrounds showed the high level of peptide nucleic acid (PNA) probe positivity indicating that the PNA-telomere probe was hybridized better with telomeres in the Terf2-null brains
Summary
Genomic instability resulting from DNA damage induced by either endogenous or exogenous insults could lead to defective neurodevelopment and neurological diseases (Lee et al 2016). Ataxia telangiectasia mutated (ATM) is one of the early responders to DNA damage, to DNA double-strand breaks (DSBs). ATM mutations cause Ataxia Telangiectasia (A-T) characterized by ataxia due to loss of Purkinje and granule cells in the cerebellum (McKinnon 2012, 2013). Ataxia-telangiectasia and RAD3related (ATR) recognizes single-stranded DNA resulting from replication stress. Seckel syndrome 1 (SCKL1) due to hypomorphic mutations in the ATR gene is characterized by microcephaly and mental retardation (Nam and Cortez 2011; McKinnon 2013). Once activated by DNA damage, ATM and ATR phosphorylate several overlapping substrates including tumor protein p53 (TP53/Trp in mice) to regulate DNA damage repair, apoptosis, and cell cycle arrest (Lee et al 2001, 2012b; Lovejoy and Cortez 2009). It is well known that ATM and ATR are required to maintain genomic integrity, the precise roles of ATM and ATR during brain development are not fully understood, especially related to neuropathology such as ataxia, neurodegeneration, and microcephaly observed in human patients
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