The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1

Abstract

Defects in DNA single strand break repair (SSBR) can cause neurodegeneration. To better understand the function of SSBR in the nervous system, the authors ablated Xrcc1 in all of the neural progenitors of developing mice. This revealed that the postnatal differentiation of several types of cerebellar interneurons is particularly dependent on SSBR. Defective responses to DNA single strand breaks underlie various neurodegenerative diseases. However, the exact role of this repair pathway during the development and maintenance of the nervous system is unclear. Using murine neural-specific inactivation of Xrcc1, a factor that is critical for the repair of DNA single strand breaks, we found a profound neuropathology that is 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 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.