One of the most challenging problems in neurobiology is to understand the mechanisms that mediate the formation of a functional neuronal network. Despite the identification of several molecules that regulate axon guidance and cell migration, it is unclear how these factors can specify a large number of connections in the nervous system.
The present project aims to study the role and mechanism of action of the Fibronectin Leucine-Rich Transmembrane (FLRT) family protein in axon guidance and cell migration during mouse central nervous system (CNS) development. The proposed fellow intends to tackle this problem using a multidisciplinary approach including conditional mouse mutant mice lacking either specific FLRT or Unc5 proteins, cell based functional assays using neurons derived from mutant mice, and molecular and biochemical assays to identify signalling pathways activated by FLRTs. Recent unpublished results from the proposed host institution, the Department of Molecular Neurobiology (Dr. Klein) at Max Planck Institute of Neurobiology, indicate that shed ectodomains of FLRTs can function as long-range guidance cues for cortical neurons in vitro and in vivo. FLRTs exert their functions by binding to Unc5 receptors. Moreover, FLRTs may also act as cell autonomous signaling receptors. Thus, FLRT proteins have the potential to engage in bi-directional signaling (‘forward’ via Unc5 receptors and ‘reverse’ via their own intracellular domain), an original and innovative concept which Dr. Klein previously pioneered in the ephrin/Eph field. Should the hypothesis of the proposed research be correct, the findings will undoubtedly represent an advance in the state of art in the neurobiology area, and also may shed light on certain neural developmental disorders.
The proposed fellow will highly benefit from the challenging research environment and supervision of a renowned scientist, which will offer him promising perspectives for his further research career in Europe.
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