Mechanisms of glia-derived neurogenesis (360G-Wellcome-095722_Z_11_A)

Classic forward genetic screens in C.elegans have revealed many evolutionarily conserved genes required to generate individual terminal neuron types. However, little attention has been paid to the molecular and cellular mechanisms that act early during embryogenesis to specify neuronal lineages. The overall goal of this research is to characterise these events. Surprisingly, one third of bilateral pairs of neurons in C. elegans derive from asymmetric lineage origins. I have identified a prone ural gene, hlh-14/achaete-scute that acts, along with other unknown factors to impose bilaterally symmetric neuronal differentiation on a pair of neuroblasts from asymmetric lineage origins. The first key goal of this project is to identify using reverse genetics, promoter analysis and laser ablation studies the cis-regulatory mechanisms and trans-acting factors that regulate early hlh-14 expression in C. elegans. The second key goal of this project, through a forward genetic screen, lineage ana lysis and second-generation sequencing based transcriptome analysis is to isolate novel factors that act to specify neuronal lineages and impose bilateral symmetry on the nervous system. This work will have broad implications for neural development in higher vertebrates and provide novel insights relevant to the prevention of human neurological disease.