Cellular and molecular mechanisms of striatal pathway development

Abstract

One of the main features of the nervous system is the presence of a highly organized network of specialized cells (i.e. neurons), which allow coordinated and integrated communication over long distances. The formation of the brain neuronal network is achieved during embryonic development, when precise axonal connections between neurons and their synaptic targets are established. This process, called axon guidance, is conserved in several species. In the last 25 years, the use of animal models led to the identification of the genes regulating the interaction of the growing axons with attractant or repellent cues, guide post cells or other axons, present along their complex trajectories. This research constitutes the fundaments needed to understand the pathogenesis of several human psychiatric and neurodegenerative disorders caused by alterations in brain connectivity. Strikingly, among the numerous axonal tracts that run along the antero-posterior (AP) axis of the brain, the development of the striatal axonal pathway remains poorly characterized. The striatum is one of the largest nuclei in the brain and it is involved in the regulation of voluntary movements and goal directed behavior. Altered striatal connectivity is found in diseases that impair decision-making, social interactions and self-awareness (e.g. autism, obsessive-compulsive disorder, schizophrenia and Huntington’s disease). This thesis explores the genetic mechanisms orchestrating striatal pathway formation and uncovers novel roles for Wnts and Fzds in the regulation of this process in the ventral telencephalon.