In the developing nervous system, nerve cells and axons respond to a variety of attractive and repulsive guidance cues en route to their final destination. On their journey they follow a complicated trajectory using in some circumstances multiple cues, in others switching their responsiveness to a particular bifunctional cue, acting over short and long range. An essential step in obtaining a better understanding of the molecular mechanisms that underlie these events is to identify receptor complexes that couple guidance cues to directed guidance. Uncovering the molecular mechanisms that translate an extracellular cue into a change in the growth cone cytoskeleton is likely to lead to a better understanding of certain developmental disorders, and also to contribute towards development of therapeutic interventions to improve nerve regeneration following injury. The central aim of this proposal is to characterize receptor complexes that mediate responses of growth cones to the bifunctional guidance cue Netrin-1 in the developing nervous system.Netrin-1 attracts several classes of axons, while repelling others. Netrin receptors of the DCC family are implicated in mediating both attraction and repulsion; in contrast members of the UNC-5 family are implicated in signaling repulsion alone or in combination with DCC. How UNC5 signals repulsion independent of DCC is not known. Here we hypothezise that UNC5 signals two types of DCC-independent repulsion, through homomultimerization of UNC5A and through heteromultimerization of UNC5B-D with the orphan receptor PUNC. We are determined to elucidate how Netrin-1 mediates axonal repulsion. We will (I) characterize DCC- independent repulsion in vertebrates spinal neurites in vitro, (II) define the receptor complexes mediating DCC independent repulsion by using a combination of biochemical and genetic approaches and (III) evaluate the function of these receptors in Netrin-1 signaling in vitro and in vivo by utilizing directional and outgrowth responses of primary neuronal cultures in combination with loss- and gain-of-function approaches. This work will provide the foundation for understanding how neurons translate a bidirectional cue, such as Netrin-1, into directed guidance. In addition, it should be of more general importance in providing insights into the underlying receptor mechanism used by bifunctional cues to guide axons during neurodevelopment. ? ?
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