Development of the cerebellum is exquisitely dependent on the Sonic Hedgehog (SHH) pathway that drives the expansion of granule cell progenitors (GCPs) and other cells. Impairment of this pathway leads to cerebellar hypoplasia. On the opposite, its untimely/excessive activation results in medulloblastoma development, supporting the oncogenic role of the pathway. SHH signal transduction largely occurs in the primary cilium (PC), an antenna-like structure enriched in receptors and other signaling molecules. This is organized by the basal body in non-mitotic cells. After PC disassembly, the same organelle organizes the centrosome, before mitotic onset. Dysfunctions of this dynamic organelle affect SHH pathway and are involved in genetic diseases known as ciliopathies, in CNS developmental diseases and cancer.
Nbs1 is a member of the Mre11/Rad50/Nbs1 complex, which is essential for genome integrity and the DNA damage response. Mutations in the Nbs1 gene cause the Nijmegen Breakage syndrome, a DDR-defective syndrome characterized by immunodeficiency, microcephaly and cancer predisposition.
Taking advantage of a CNS restricted Nbs1 knock-out mouse model, we recently demonstrated that Nbs1-KO abrogates tumorigenesis in a spontaneous model of SHH-MB and impairs the growth of SHH-MB allografts. Inducible Nbs1-KO inhibits the SHH-pathway in developing GCPs, in vivo and in vitro. Hints from the literature and our preliminary data suggest that Nbs1 may exert previously unrecognized functions on the PC, thus affecting SHH-dependent cerebellar development and tumorigenesis.
In this project we will develop new animal and cellular models to specifically address this hypothesis and we will integrate these studies with dynamic biochemical and imaging analysis of PC structure and function.
We believe that disclosing a novel role for Nbs1 on PC and SHH pathway may provide new insights into different genetic diseases affecting cerebellar development and cancer.
