STRUCTURAL DETERMINANTS OF TRK RECEPTOR SPECIFICITIES USING BDNF-BASED NEUROTROPHIN CHIMERAS

Neurotrophins play very important roles in the development and mainten ance of the vertebrate nervous system. In mammals, there are four memb ers of the family: NGF, BDNF, NT-3, and NT-4/5. Members of the neurotr ophin family activate different receptors that belong to a class of re ceptor tyrosine kinases known as ''Trks.'' For example, NGF is the spe cific ligand of TrkA, while BDNF activates TrkB. To elucidate which re gions specificities, chimeric neurotrophins were constructed using BDN F as the backbone, with various regions being substituted by the corre sponding regions of NGF. The activity of the chimeras of the Trk recep tors was assayed in transfected fibroblasts ectopically expressing the Trk receptors. Our findings revealed that, although BDNF is absolutel y conserved in mammals, substitution of several small variable regions from NGF into the BDNF backbone did not lead to significant loss in T rkB activity or gain in TrkA activity. Moreover, important determinant s of TrkB activation might be located in the carboxy-terminal half of BDNF. On the other hand, critical elements for TrkA activation might b e located within the amino-terminal half of the mature NGF molecule. ( C) 1996 Wiley-Liss, Inc.