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 GCPs in 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 a Tis21-dependent manner (Patched1+/−/Tis21 wild-type vs. Ptch1+/−/Tis21 knockout), 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 the Tis21-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.
Highlights
About 30% of medulloblastomas (MBs), the pediatric tumor of the cerebellum, originates from the granule neuron precursor cells (GCPs) located in the external granular layer (EGL), at the surface of the developing cerebellum, in consequence of hyperactivation of the Sonic Hedgehog (Shh) pathway (Kadin et al, 1970; Schüller et al, 2008; Yang et al, 2008; Gibson et al, 2010; Northcott et al, 2012)
If we analyze the type of expression changes occurring in the whole array of genes of Set A that either directly or indirectly regulate the proliferation and/or the cell cycle of the GCPs (Table 7) we find that there is upregulation as well downregulation of genes that affect either positively or negatively this process, resulting in no net change of proliferation of the GCPs
We have shown a link between the Shh signaling, operating through the primary cilium, and the impairment of cell migration, i.e., the main phenotype observed in Ptch+/−/Tis21KO mice [17]
Summary
About 30% of medulloblastomas (MBs), the pediatric tumor of the cerebellum, originates from the granule neuron precursor cells (GCPs) located in the external granular layer (EGL), at the surface of the developing cerebellum, in consequence of hyperactivation of the Sonic Hedgehog (Shh) pathway (Kadin et al, 1970; Schüller et al, 2008; Yang et al, 2008; Gibson et al, 2010; Northcott et al, 2012). Whole-genome analyses of expression and function indicated that the key molecule responsible for the lack of migration of GCPs is the chemokine Cxcl (Farioli-Vecchioli et al, 2012a). The set of genes whose expression significantly differs in the comparison Ptch1+/−/Tis wild-type vs. Ptch1+/−/Tis21KO will be hereafter defined as Set A (Figure 1)
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