The long-term goals of this study are to understand how neurotrophin growth factors regulate the normal development and function of the vertebrate visual system. The neurotrophin BDNF supports the survival of retinal and tectal neurons, as well as guiding the local growth of axonal and dendritic processes and regulates synaptic function in an activity-dependent manner. The actions of BDNF are mediated principally by the trkB receptor, expressed widely in the retina, tectum and other visual nuclei. A critical unresolved issue is how the trkB receptor mediates these pleiotropic responses to BDNF. The applicant's discovery of the complex splicing of trkB receptors in the visual system indicates that receptor binding and signal transduction are tightly regulated at the level of receptor structure. Advancing our understanding of the diverse roles of BDNF in the visual system will require the characterization of the functional properties and expression patterns of the trkB receptor isoforms.
The specific aims are focused on the three major classes of trkB splice variants expressed in the visual system.
Aim 1 will examine how alternative splicing in the extracellular binding domain (ED motif) regulates neurotrophin specificity and receptor activation.
Aim 2 will determine the effects of a cytoplasmic insertion (JI motif) on receptor kinase activity, activation of signaling pathways and downstream cellular responses.
Aim 3 will determine the expression of Kinase Deletion (KD) isoforms in the retina and their potential role as inhibitors of the full length (FL) receptor function in vitro and in vivo. BDNF is a promising agent for promoting retinal cell survival and optic nerve regeneration following eye injury and disease. An important contribution to the development of its therapeutic potential will come from the characterization of trkB receptor isoforms and their functional properties.
| Boeshore, K L; Luckey, C N; Zigmond, R E et al. (1999) TrkB isoforms with distinct neurotrophin specificities are expressed in predominantly nonoverlapping populations of avian dorsal root ganglion neurons. J Neurosci 19:4739-47 |
| Oakley, R A; Garner, A S; Large, T H et al. (1995) Muscle sensory neurons require neurotrophin-3 from peripheral tissues during the period of normal cell death. Development 121:1341-50 |
| Garner, A S; Large, T H (1994) Isoforms of the avian TrkC receptor: a novel kinase insertion dissociates transformation and process outgrowth from survival. Neuron 13:457-72 |
