The generation of neurons during development from a fertilised egg requires a cascade of neuronal lineage-specific genes. This genetic cascade, and in particular the expression of proneural genes, is also required for efficient in vitro reprogramming of adult cells into neuronal cells for replacement therapies. Yet the upstream molecular events that directly regulate the expression of proneural transcription factors during embryogenesis remain ambiguous. The specification of neuronal lineages is further complicated by the fact that it needs to be coordinated across the left-right (L/R) axis. Our nervous system, like our body, is largely bilaterally symmetric yet both molecular and anatomical L/R asymmetries are also observed in the brain. Disruptions of bilateral and L/R asymmetric organisation in the human brain are frequently observed in Parkinson’s disease, schizophrenia and epilepsy. How symmetric and asymmetric neural determination programs are coordinated to establish a fully functional nervous system is poorly understood.
The first key aim of this proposal is to identify the cis-regulatory mechanisms and trans-acting factors that control both symmetric and asymmetric proneural gene expression in C. elegans using a combination of in vivo promoter analysis and reverse genetics. The second key aim of this proposal is to identify and characterise through forward genetic screens, 4D-lineage analysis and second-generation sequencing approaches, novel factors that act in two specific neuronal lineages to either (a) impart bilaterally symmetric neurogenesis or (b) regulate asymmetric neurogenesis. Since many principles of neural development are conserved from nematodes to vertebrates, defining in more detail the early steps of bilaterally symmetric and asymmetric neurogenesis in vivo in this genetic model system will allow us to generate neurons in vitro more efficiently and will advance our understanding and prevention of human neurological disease.
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