Mental disorders constitute a human and economic burden for developed countries. Many mental disorders have been linked to serotonin dysfunction, but the precise mechanisms underlying these defects are not well understood. Serotonin Related Mental Disorders (SRMD) are multigenic, which makes the identification of these mechanisms a very difficult task. Understanding the molecular mechanisms that generate serotonergic neurons may provide the tools required for the identification of the mutations that would predispose to SRMD. In this grant we will use a multidisciplinary approach to dissect the transcriptional mechanisms that generate serotonergic neurons. Serotonergic neurons are very ancient in evolution and enzymes and transporters responsible for the production of serotonin (serotonin pathway genes) are highly conserved in all metazoans. We will take advantage of this evolutionary conservation and use the genetic amenability of C. elegans to dissect the genetic mechanisms responsible for the generation of the serotonergic neurons. Next, we will apply the lessons learned from C. elegans to unravel analogous mechanisms regulating mouse serotonergic differentiation. Our preliminary results show that the serotonergic pathway genes are co-regulated by the same factors, and that this mechanism is evolutionary conserved. We will identify the cis-acting sequences (serotonergic motif) and trans-acting factors responsible for the activation of the serotonergic features, both in worms and mice. Finally, we will apply our knowledge on serotonergic differentiation to generate serotonergic neurons in vitro. If successful, this project should lead to (i) the identification of the fundamental mechanisms underlying the specification of serotonergic neurons, and (ii) the generation of new tools to understand and treat SRMD.
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