Analysis of the function and intracellular signal transduction mechanism of secreted semaphorins during neural circuit development

Our ability to perceive, to act and to remember is a reflection of the elaborate synaptic connections and neuronal circuits that make up the brain. The formation of these connections relies on a series of developmental events including axon growth and guidance, synapse formation and cell death. The occurrence of defects in these events is thought to lead to mental disorders such as schizophrenia or autism. Neuronal circuits and synaptic contacts established during development are maintained during adulthood. Loss of connectivity in the adult brain is a hallmark of neurodegenerative disorders such as Parkinson's disease or amyotrophic lateral sclerosis (ALS). Insight into the cellular and molecular processes that normally control the formation and maintenance of neuronal conections will help to further understand situations of perturbed connectivity during disease and may provide new leads for therapeutic intervention. The aim of this thesis is to further our understanding of the functional roles of a large family of axon guidance cues, the semaphorins, during nerual circuit development (part1) and to characterize the signaling pathways that operate downstream of semaphorins in neurons (part2). In part 1 we show a novel and important role for semaphorin 3F (Sema3F) and its receptor neruopilin 2 (Npn2) in the formation of the axonal projections from the ventral tegmental area towards the prefrontal cortex (medial forebrain bundel). These projections are involved in cogitive functions and are altered in mental disorders such as autism and schizophrenia. We further show that Sema3F is not only a repellent cue, as demonstrated previously by several groups, but can also attract axons. Furthermore, we show that Sema3F not only acts through Npn2, but also through a new unidentified receptor. In part 2 of this thesis the focus is shifted to the intracellular signaling protein MICAL, which is thought to act downstram of semaphorin signaling. Here we investigated the expression pattern and analyzed the role for MICAL proteins in axon projection formation. We show that certain brain area's form an attractive neural system to further examine the role of MICAL proteins. Furhermore, we show how MICAL proteins can affect axonal projections required for memory and which are effected in disorders like stress and epilespy. In all, the results from the work discribed in this thesis form a valuable framework for future studies on semaphorins and MICALs in physiological (cognition and memory) and pathological processes (autism, schizophrenia, epilepsy and stress).