This proposal concerns the study of transcriptional regulation of neurotrophin receptors during mouse development. Trk family of receptor tyrosine kinases and their ligands, the nerve growth factor family of neurotrophins, have been implicated in neuronal survival and differentiation. Neurotrophins have been considered as potential therapeutic agents for neurodegenerative diseases including Alzheimer's as well as for spinal cord injury. However, little is known about the regulation of expression of these genes. We recently identified a trkA enhancer that is necessary and sufficient to drive an Hsp68 minimal promoter to express with fidelity the in vivo pattern of trkA expression. A novel member of the Kruppel-like transcription factors (NKLF for neurogenic Kruppel like factor) was identified to bind this trkA enhancer. In the First Aim, expression of NKLF in vivo will be studied. In the Second Aim, the DNA binding and transactivation properties of NKLF will be characterized in vitro. In the Third Aim, the ability of NKLF to activate trkA enhancer will be tested in cell cultures. In the Fourth Aim, the in vivo function of NKLF will be studied by gene targeting in mice. In the Fifth Aim, we propose to expand the library screen to identify other transcription factors that regulate trkA expression.
