TRNR2, A NOVEL RECEPTOR THAT MEDIATES NEURTURIN AND GDNF SIGNALING THROUGH RET

Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) comprise a family of TGF-P-related neurotrophic factors (TRNs), which have trophic influences on a variety of neuronal populations. A recep tor complex comprised of TrnR1 (GDNFR alpha) and Ret was recently iden tified and found to be capable of mediating both GDNF and NTN signalin g. We have identified a novel receptor based on homology to TrnR1, cal led TrnR2, that is 48% identical to TrnR1, and is located on the short arm of chromosome 8. TrnR2 is attached to the cell surface via a GPI- linkage, and can mediate both NTN and GDNF signaling through Ret in vi tro. Fibroblasts expressing TrnR2 and Ret are similar to 30-fold more sensitive to NTN than to GDNF treatment, whereas those expressing TrnR 1 and Ret respond equivalently to both factors, suggesting the TrnR2-R et complex acts preferentially as a receptor for NTN. TrnR2 and Ret ar e expressed in neurons of the superior cervical and dorsal root gangli a, and in the adult brain. Comparative analysis of TrnR1, TrnR2, and R et expression indicates that multiple receptor complexes, capable of m ediating GDNF and NTN signaling, exist in vivo.