Expansion of outer cortical layer Cux2+ neurons required selective adaptations for DNA repair

During mammalian evolution, upper cortical layer 2/3 excitatory neurons have shown a disproportionate expansion compared to other layers. Replicative expansion of cortical neural progenitors is associated with significant oxidative DNA damage. Here we show that Activating Transcription Factor 4 (Atf4) has new roles as a critical regulator of the DNA Damage Response, directly activating components of double stranded DNA repair, including CIRBP, Uba52 and Ebf1. Strikingly, pan-cortical knockout (Emx1cre, Atf4fl/fl) demonstrates that Atf4 is specifically required for development of upper layer 2/3 neurons, marked by expression of CUT-homeodomain protein, Cux2. Atf4 functions to repair DNA damage and attenuate cell death of embryonic radial glial progenitors in a p53-dependent manner. In particular, we show that Cold-Inducible RNA-Binding Protein (Cirbp) is a transcriptional target of Atf4 that is required for the normal phosphorylation of the key double strand DNA repair factor Ataxia-Telangiectasia Mutated (ATM). These findings establish that Atf4 is an essential regulator of the DNA Damage Response. They further indicate extraordinary requirements for DNA repair post-replicative stress in Cux2+ neurons during mammalian brain development.