To achieve complex functions, even simple nervous systems require a sophisticated
degree of specialization in labor giving rise to the most complex cellular diversity found in any
organ. Understanding the mechanisms guiding neuronal specification programs remains a major challenge. Importantly, failure to properly implement these genetic programs is linked to several neuropsychiatric and neurodegenerative diseases.
In this project we use the nematode C. elegans, an essential animal model for its simplicity and amenability to genetic modifications, for studying the general principles of neuron specification, to provide important insights to four fundamental questions:
1) First, how are neuron-type specific regulatory landscapes shaped 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. In this project we propose to develop a new tool to study in vivo TF binding profiles in a cell-type specific manner. This tool will allow us to better understand the function of TFs in different neuron types. We also expect it could be of great use to other groups in the C. elegans community.
2) Second, 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. Once again, availability of tools limits our capability to move forward in the understanding of how information is stored in the non-coding genome. In this grant we are trying to develop massively parallel reporter assays and bioinformatics to begin decoding the rules of the neuronal
regulatory genome.
3) Third, we expand from transcriptional regulation to other layers of complexity and have started studying the involvement of the basic translational machinery in neuronal differentiation processes. 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) Finally, we are also studying how new types of neurons emerge during evolution. In this part of the project we use different species of Caenorhabditis nematodes to explore how the gene regulatory networks, that have been extensively characterized in C. elegans, are modified in other species.
We expect that results from this project 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. This knowledge can also be important in the development of new therapeutic strategies to treat diseases of the nervous system.
