Neuronal Src kinases: oncogenes in brain development?

The challenges of the developing human brain include co-ordinating the birth and migration of 100 billion neurons and the formation of their 1000 trillion synaptic connections. Protein phosphorylation by kinase enzymes is one of the mechanisms that orchestrates these processes. The ubiquitous and highly conserved C-Src tyrosine kinase is enriched in the brain and there is neuronal-specific splicing of C-Src to yield two further isoforms, N1-Src and N2-Src. The neuronal splice insertions in the N-Srcs render the kinases constitutively active, much like oncogenic mutations of C-Src that drive tumourigenesis in cancer. We and others have shown that the neuronal Srcs play a role in both neurogenesis and neuronal differentiation during development, but their downstream signalling is poorly understood. This project will draw on expertise in kinase signalling and neuronal gene expression in the Evans and Chawla labs to discover how N1- and N2-Src drive the differentiation of neuronal progenitors. Recent interaction, substrate and transcriptomic screens in the lab have identified several promising N-Src targets to pursue. Training will be provided in a wide range of molecular cell biology and protein biochemistry approaches. The data arising from this project will inform fundamental mechanisms of neuronal development, but will also be applicable to optimising the differentiation of neural stem cells for research and therapeutic use.
Relevant publications:
Lewis PA et al. (2017) J Neurosci. 37(35):8477-8485
Keenan S et al. (2017) Sci. Rep. 7, 43106
Keenan S et al. (2015) FEBS Lett, 589(15), 1995-2000