Genetic analysis of neural crest migration: Requirement of Dapper2-mediated inhibition of the Wnt canonical activity

Abstract

Numerous initiatives to improve our understanding of cancer biology have been lunched in different laboratories that aim to describe the interactome and gene-expression profile in different tumour cell line. It is now clear that the different strategies of cell migration observed in cancer are reminiscent of the different migratory strategies observed during embryo development. These similarities suggest that developmental program that has to be kept off after embryogenesis may be induced by spontaneous genetics modifications that produce tumour cells.

In this study we went inside the genetic network/profile that controls how neural crest cells eventually switch on the migration program and how they are able to arise into different lines with the propose of getting new ideas on how to prevent dissemination of tumour cells or how to treat advanced tumour that have already spread.

Neural progenitors of the dorsal neural tube that acquire the expression of specific neural crest determinants, delaminate from the neural tube and follow precise migratory pathways, to terminally differentiate into the various neural crest derivatives. Here we developed a novel resource for lineage trace and isolation of neural crest cells that allowed for a genome-wide expression screen in pre-migratory and migratory neural crest progenitors. We efficiently identified previously known neural crest specific genes. Expression profiling revealed new neural crest genes belonging to a wide range of cellular functions, with high representation of genes associated to cell motion. Additionally, we identified chick genes for which the human orthologues and/or paralogues are associated to Neuroblastoma formation.

In my thesis we identified new genes specifically expressed in the developing neural crest, and proposed a revised genomic signature for the normal neural crest cells. Furthermore, mutations on some of these genes are markers for Neuroblastoma tumour formation. Thus we propose this as a valid screen to identify candidates genes that contribute to the characterization of the Neuroblastoma cancer stem cells, and thus to the identification of specific targets to design new therapeutic strategies.

Getting in more detail into this genetic network, Wnt canonical signalling response has to been shown to be a key event in both cancer and neural crest cell development. Traditionally Wnt canonical pathway has been involved in neural crest induction process, but here we demonstrated that it is also critical for the onset migration of the neural crest cell. In fact, high levels of Wnt canonical activity prevents neural crest cell to delaminate and only through the inhibition of this activity mediate by dapper protein, neural crest cells can undergo into their normal migration pathways. If this process has an implication in cancer is still unknown, but Dapper expression proteins have been already associated to different types of cancer.