Genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1

Defective responses to DNA single strand breaks underpin various neurodegenerative diseases. However, the exact role of this repair pathway during development and maintenance of the nervous system is unclear. Using murine neural-specific inactivation of Xrcc1, a factor critical for the repair of DNA single strand breaks, we identified a profound neuropathology characterized by the loss of cerebellar interneurons. This cell loss was linked to p53-dependent cell cycle arrest and occurred as interneuron progenitors commenced differentiation. Loss of Xrcc1 also led to the persistence of DNA strand breaks throughout the nervous system and abnormal hippocampal function. Collectively, these data detail the first in vivo link between DNA single strand break repair and neurogenesis, and highlight the diverse consequences of specific types of genotoxic stress in the nervous system.