NBS1 is a member of the MRE11/RAD50/NBS1 (MRN) complex, which plays an essential role in maintenance of genome integrity and in the DNA damage response (DDR). Mutations in its gene lead to the Nijmegen Breakage syndrome (NBS, OMIM-251260), a human DDR-defective syndrome characterized by immunodeficiency, microcephaly and cancer predisposition. The neurological features of NBS patients have been modelled in a mouse with central nervous system (CNS) restricted NBS1 knock-out (Nbn-CNS-del mouse), which shows microcephaly, severe ataxia and cerebellar hypoplasia. In the cerebellum, the SHH pathway is the main driver of granule cell progenitors (GCPs) proliferation,
but, if hyper-activated, also leads to transformation into medulloblastoma (MB). Strikingly, mice with CNS-conditional Sonic Hedgehog (SHH)-KO show a phenotype similar to Nbn-CNS-del mice, suggesting functional links between these pathways.
Interestingly, it has recently been shown that many DDR proteins localize and regulate centrosome dynamics through the cell cycle. Moreover, defects in centrosome-associated factors that function in DDR processes give rise to a range of human inherited disorders that include several microcephalic disorders and ciliopathies. Notably, during interphase the centrosome converts into the basal body of the primary cilium, a key organelle essential for the proper transduction of numerous signaling pathways during development, including the SHH one.
Our work thereby aims to provide new insights into the emergent role of NBS1 on PC and SHH pathway which could shed a light on the striking neurological phenotypes that manifest in the rare human disorder Nijmegen Breakage Syndrome and will further increase our understanding of the role of DDR proteins in neuronal development.
The in-depth study of a new functional role exerted by NBS1 on the PC and consequently on the SHH pathway could open doors to the comprehension of the neurological phenotypes that manifest in DDR-defective syndromes such as the Nijmegen Breakage Syndrome. Pre-existing literature supports the idea that DDR proteins could exert functions which are not necessarily related to their canonical role in DNA damage. Our study should reveal the molecular mechanisms that lie at the basis of the connection between this still unidentified role of DDR proteins and cerebellar development.
By demonstrating a direct effect of NBS1 on ciliary morphology/functionality and on the SHH pathway, we will not only potentially discover a novel role for this protein, extraneous to its well-established function in DDR, but we could also offer a possible causal explanation to the severe cerebellar developmental deficiencies observed in our Nbnfl6/fl6:Gli1-CreER mouse model. Moreover, these results will give us a deeper insight into the neurological phenotypes observed in patients affected by Nijmegen Breakage Syndrome. The possible confirmation of our hypothesis could thus provide an explanation for the observed microcephalic phenotype triggered by the PC-dependent downregulation of the SHH pathway in cells deficient for NBS1 further elucidating the connection between DDR proteins and neuronal development and providing new insights into rare human disorders such as the Nijmegen Breakage Syndrome.