Dissecting new functions of the Nijmegen breakage syndrome gene in cerebellar development

The Nijmegen Breakage Syndrome is a rare inherited syndrome characterized by microcephaly, defective immune responses and cancer predisposition due to mutation of NBS1, a component of the MRN complex. It exerts essential functions in preventing the accumulation of toxic byproducts coming from replication which may transform into damaged DNA and threaten genomic stability and survival of multiple cell lineages, and in particular of neuronal progenitor cells. While the other manifestations of the disease appear coherent with this interpretation, the striking sensitivity of the nervous system to this genetic defect compared to other tissues is far less understood. Our preliminary data and scattered evidences from the scientific literature allowed us to put forward an innovative hypothesis, which suggest that NBS1 might exerts additional and yet undisclosed functions on nervous system developmental pathways. In this project we describe a full set of experimental procedures making use of multiple on-purposed developed experimental models which should allow to unequivocally prove the accuracy of our hypothesis. NBS neurological phenotype has no cure, at the present. Although we are unable to propose a therapeutic strategy at the moment, we are fairly confident that only a significant step forward in understanding its molecular basis may allow the design of an appropriate intervention strategy, in a close future.