Regulatory rules and evolution of neuronal gene expression

ongoing

Complex brain functions require a remarkable degree of cellular specialization. Understanding the mechanisms guiding neuronal specification programs remains a major challenge. Here we use the nematode C. elegans, an essential animal model for studying the general principles of neuron specification, to provide answers to four fundamental questions: 1) How are regulatory landscapes coordinately activated in each type of neuron? We previously showed that complex combinations of transcription factors (TFs) implement neuron-type specific programs. TF behaviour at the genome-wide level is not well-understood. Our expertise on dopaminergic and serotonergic neuron specification will be instrumental in answering this question. 2) How are TF interactions mirrored by syntax rules of the regulatory genome? Our preliminary data demonstrate extensive TF-TF cooperativity that is mirrored by specific syntax in the target enhancers. We will use massively parallel reporter assays and bioinformatics to begin decoding the rules of the neuronal regulatory genome. 3) Does regulation of basic translational machinery play a role in neuronal differentiation? The mechanisms regulating the basal translational machinery are emerging as a new dimension in the regulation of cell type specification. We recently found the conserved translation initiation factor eIF3A is required for serotonergic terminal differentiation, opening the door to the study of this novel regulatory role for eIF3 complex. 4) How do new types of neurons emerge during evolution? We will combine our unique expertise on neuron specification with the amenability of the Caenorhabditis species and novel single-cell technologies to unravel the regulatory mechanisms underlying the appearance of new neuronal types in evolution. Our work will unravel novel principles on the regulation of neuronal specification and the evolution of cell types in the nervous system, fundamental for our understanding of brain development and function.