Nervous system development

Whereas vitamin A is best known for its critical role during embryonic development and visual cycle (documented by 3 Nobel prizes), its post-natal activities, including in neuroprotection, modulation of neurotransmission and synaptic plasticity only start being discovered and understood. Our goal is to decipher the highly diverse functions of vitamin A, its active derivatives (retinoic acids), and the corresponding nuclear receptors (RARs/RXRs), in neural development, aging, and in stem cell control. Our studies of specific retinoid receptors and bioactive metabolites in control of diverse biological processes should contribute to a better understanding of the mechanisms underlying development and function of specific cell types and relevant neural circuits. We also investigate the therapeutic potential of specific retinoids in neurological and psychiatric diseases.

To address these questions, we use genetic, pharmacological or behavioral mouse models of specific diseases, as well as CRISPR- and viral-based approaches to control gene expression. Our mechanistic studies are guided by combination of genomic, proteomic and metabolomic data from clinics and mouse models. In collaboration with experts in chemistry we also develop new tools to study biological processes in vivo (e.g. click chemistry, novel RXR agonists). We have shown that fine-tuning of retinoic acid activity depends on its spatiotemporal patterns of synthesis (by retinol and retinaldehyde dehydrogenases) and catabolism (by CYP26 enzymes).

Our current focus relates to the role of retinoids in brain physiology and pathology, with a particular interest in basal ganglia and dopaminergic signaling, whose dysfunctions are associated with several neuropsychiatric disorders. These studies take advantage of murine models relevant to neurodevelopmental disorders, Parkinson and Huntington diseases, and depression. We also investigate mechanisms of glial cell development and biology to elaborate regenerative medicine approaches in multiple sclerosis.  A long-term goal is to understand the mechanisms underlying these disorders, and develop new strategies or compounds for their prevention or therapy.