The Role of Ku70 in Regulating Cell Death During Cerebral Cortical Development

Ku70’s role in DNA repair is well-characterized and is critical for neuronal survival during cortical neurogenesis. Mice deficient in DNA repair exhibit elevated cell death of immature neurons during neurogenesis, demonstrating that young neurons have a high requirement for DNA repair. More recently, Ku70 has been demonstrated to bind and sequester Bax, a pro-apoptotic member of the Bcl-2 family, and prevent Bax from translocating to the mitochondria to initiate the intrinsic cell death mechanism. First, we identified dying cells in the Ku70 null cortex as immature, migrating neuroblast. Then, we utilized in utero electroporation of a mutant construct of Ku70 (Ku70 Δ60) in Ku70 null embryos to investigate whether deficiency in DNA repair or loss of Bax regulation were vital for cell survival during corticogenesis. The mutant Ku70 is truncated at the N-terminus, which is crucial for its DNA binding and DNA repair function, while the Bax binding domain is retained at the C-terminus. Electroporation of both wildtype Ku70 and Ku70 Δ60 resulted in a 50% decrease in cell death compared to negative control, suggesting that Ku70’s mediates cell death during cortical development via its cytoprotective function. This