title: Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development.
abstract: We have recently generated a novel medulloblastoma (MB) mouse model with activation of the Shh pathway and lacking the MB suppressor Tis21 (Patched1+/-/Tis21KO). Its main phenotype is a defect of migration of the cerebellar granule precursor cells (GCPs). By genomic analysis of GCPsin vivo, we identified as drug target and major responsible of this defect the down-regulation of the promigratory chemokine Cxcl3. Consequently, the GCPs remain longer in the cerebellum proliferative area, and the MB frequency is enhanced. Here, we further analyzed the genes deregulated in aTis21-dependent manner (Patched1+/-/Tis21wild-type vs.Ptch1+/-/Tis21knockout), among which are a number of down-regulated tumor inhibitors and up-regulated tumor facilitators, focusing on pathways potentially involved in the tumorigenesis and on putative new drug targets. The data analysis using bioinformatic tools revealed: (i) a link between the Shh signaling and theTis21-dependent impairment of the GCPs migration, through a Shh-dependent deregulation of the clathrin-mediated chemotaxis operating in the primary cilium through the Cxcl3-Cxcr2 axis; (ii) a possible lineage shift of Shh-type GCPs toward retinal precursor phenotype, i.e., the neural cell type involved in group 3 MB; (iii) the identification of a subset of putative drug targets for MB, involved, among the others, in the regulation of Hippo signaling and centrosome assembly. Finally, our findings define also the role of Tis21 in the regulation of gene expression, through epigenetic and RNA processing mechanisms, influencing the fate of the GCPs.
authors.affiliation: Institute of Neurological Sciences, National Research Council Catania, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Gentile
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Ceccarelli
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Micheli
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia Rome, Italy.
authors.forename: Felice
authors.initials: F
authors.lastname: Tirone
authors.affiliation: Institute of Neurological Sciences, National Research Council Catania, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Cavallaro
keywords: Sonic Hedgehog; cerebellar precursor cell; chemokines; drug target; medulloblastoma model; neural migration; primary cilium; retina