Cockayne syndrome b maintains neural precursor function

Abstract

Neurodevelopmental defects are observed in the hereditary disorder Cockayne syndrome (CS). The gene most frequently mutated in CS, Cockayne Syndrome B (CSB), is required for the repair of bulky DNA adducts in transcribed genes during transcription-coupled nucleotide excision repair. CSB also plays a role in chromatin remodeling and mitochondrial function. The role of CSB in neural development is poorly understood. Here we report that the abundance of neural progenitors is normal in Csb−/− mice and the frequency of apoptotic cells in the neurogenic niche of the adult subependymal zone is similar in Csb−/− and wild type mice. Both embryonic and adult Csb−/− neural precursors exhibited defective self-renewal in the neurosphere assay. In Csb−/− neural precursors, self-renewal progressively decreased in serially passaged neurospheres. The data also indicate that Csb and the nucleotide excision repair protein Xpa preserve embryonic neural stem cell self-renewal after UV DNA damage. Although Csb−/− neural precursors do not exhibit altered neuronal lineage commitment after low-dose UV (1J/m2) in vitro, neurons differentiated in vitro from Csb−/− neural precursors that had been irradiated with 1J/m2 UV exhibited defective neurite outgrowth. These findings identify a function for Csb in neural precursors.