TrnR2, a Novel Receptor That Mediates Neurturin and GDNF Signaling through Ret

Abstract

Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) comprise a family of TGF-beta-related neurotrophic factors (TRNs), which have trophic influences on a variety of neuronal populations. A receptor complex comprised of TrnR1 (GDNFR alpha) and Ret was recently identified and found to be capable of mediating both GDNF and NTN signaling. We have identified a novel receptor based on homology to TrnR1, called 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 vitro. Fibroblasts expressing TrnR2 and Ret are approximately 30-fold more sensitive to NTN than to GDNF treatment, whereas those expressing TrnR1 and Ret respond equivalently to both factors, suggesting the TrnR2-Ret complex acts preferentially as a receptor for NTN. TrnR2 and Ret are expressed in neurons of the superior cervical and dorsal root ganglia, and in the adult brain. Comparative analysis of TrnR1, TrnR2, and Ret expression indicates that multiple receptor complexes, capable of mediating GDNF and NTN signaling, exist in vivo.

Receptors that mediate cellular dependence

“…The receptor complexes include RET and various glycosylphosphatidylinositol (GPI)-anchored proteins that are required for RET dimerization; these GPI-anchored co-receptors include GFRa-1, 2, 3, and 4. 55 RET and GFRa-1 transduce a GDNF signal that plays a role in the development of the enteric nervous system and the kidney; thus, null mutations in GDNF, RET, and GFRa-1 display similar phenotypes. [56][57][58] Ligand binding to the RET complex triggers RET autophosphorylation, followed by interaction with effectors that include phospholipase Cg, Shc, Enigma, Grb2, Grb7/Grb10, Src kinase, and Ras-GAP, and resultant downstream signaling.…”

GDNF/Ret signaling and the development of the kidney

“…1a). (19)(20)(21)(22) Once the UB emerges (Fig. 1b) and begins to branch, Ret expression is downregulated in the WD and the UB trunks, and becomes restricted to the distal tips of the branches (Fig.…”

“…Gfra1 is coexpressed with Ret, consistent with its role as a co-receptor, and it can also mediate GDNF signaling independently of Ret in some circumstances. (23)(24)(25) Although Gfra1 is expressed in a slightly broader domain of the UB, and also to some extent in the mesenchyme and forming nephrons, (21,22,26) its expression in cells outside the Ret domain is entirely dispensable for normal kidney development; this was shown by targeting Gfra1 coding sequences into the Ret locus, so it was expressed in the pattern of Ret, and crossing these mice to animals lacking endogenous Gfra1. (27) The key role of GDNF and its receptors in kidney development was initially revealed by the targeted disruption of the Ret, GDNF and Gfra1 genes.…”

A novel type of mutation in the cysteine rich domain of the RET receptor causes ligand independent activation

“…It has been shown that the glial cell line-derived neurotrophic factor (GDNF), neurturin (NTN) and persephin are functional ligands for the RET receptor (Durbec et al, 1996;Baloh et al, 1997;Milbrandt et al, 1998). Activation of the tyrosine kinase is mediated by glycosylphosphatidylinositol-(GPI)-anchored cell surface RET-coreceptors GDNFR-a1 ± 3 (Treanor et al, 1996;Jing et al, 1996;Baloh et al, 1997).…”