Signalling networks for stemness and tumorigenesis

Research / Instructive signals

ES-derived neural stem cells can be maintained in vitro and differentiated in various neuron-glial cells recapitulating events of neural development. Understanding how to manipulate ES-derived neural stem cells opens new opportunities to 1) model neurogenesis in vitro and study neural lineages induction-specification, 2) generate clinically relevant neurons for cell-based therapies of neuropathologies. Neural development is controlled by limited set of secreted signals (e.g. Bmps, Shh, Fgfs and Hgf) that function alone or in combination at different time points to establish neural cell fate. Action of such signals is fine-tuned by heparan sulphate proteoglycans, as Glypicans (Gpcs) that by modulating signal threshold and binding to cell membrane receptors control biological responses in targeted cells. We are investigating how extracellular signals control self-renewal, maintenance and differentiation of neural progenitors and neurons, using mutant ES cells carrying a loss-of-function mutation in the gpc4 gene.


Our previous work has revealed that in neurons the HGF/Met system predominantly acts as potentiator of other signals to enhance specific biological responses. For example, Met enhances: 1) GDNF-induced pea3 motor neuron specification by regulating their recruitment; 2) NGF-trophic support on sensory neurons, and 3) NGF-promoted survival and differentiation of sympathetic neurons. It has been shown that Met is expressed by neural precursors and promotes proliferation and differentiation of neurospheres derived by ES cells. By employing gain- and loss-of-function strategies, we are exploring whether HGF potentiates instructive/maintenance/survival signals in neural cells and neurons both in vitro and in vivo.



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last updated 13/10/2017