Isoform-specific Ras function during development. (360G-Wellcome-092791_Z_10_A)

Ras proto-oncogenes are key signalling intermediates controlling cell proliferation, differentiation and survival. Whilst most attention has focussed on the role of aberrant Ras signalling in cancer, normal Ras function is critical for embryonic development. Intriguingly, this process appears to be differentially dependent on individual Ras isoforms for reasons that remain unclear. Our study will characterise: 1. Tissue-specific gene expression and protein abundance patterns of Ras isoforms during early mouse development. 2. The contribution of Ras isoform-specific signalling networks to early embryonic development. 3. What signalling networks are engaged by Ras mutations associated with developmental disorders compared to those engaged by classical oncogenic mutations. This will allow us to ask whether and how different Ras isoforms contribute to the development of different tissue lineages and lead us to mechanistic insights into the specific pathways regulated by Ras isoforms to promote differentiation versus stemness. In later work we will develop isogenic cell models containing HRAS or KRAS mutations associated with developmental disorders. These mutations are believed to be less potent than oncogenic mutations; we will investigate whether this is the case and how this translates into differential coupling to Ras effector pathways.