Expression of GDNF Family Receptor Components during Development: Implications in the Mechanisms of Interaction

Abstract

Glial cell line-derived neurotrophic factor (GDNF) and a related factor, neurturin, promote survival of diverse groups of neurons. Both GDNF and neurturin signal via a two-component receptor complex that consists of a ligand-binding GDNF family receptor (GFRalpha-1 or GFRalpha-2) and the receptor protein tyrosine kinase Ret. Recently, a third receptor related to GFRalpha-1 and GFRalpha-2 has also been isolated and designated GFRalpha-3. Although much is known about the interaction among GDNF family factors, Ret, and the alpha-receptors in vitro, it remains unclear about their interactions in vivo. We show here by in situ hybridization that Ret and the alpha-receptors may be colocalized in the same tissues or expressed separately in projecting and target tissues, respectively, indicating that two distinct modes of interaction between Ret and the alpha-receptors exist in vivo. First, Ret may interact with the alpha-receptors expressed in the same cells (termed interaction "in cis") in many tissues and cell populations that respond to GDNF and/or neurturin, such as the substantia nigra, dorsal root ganglia, spinal cord motoneurons, kidney, and intestine. Second, Ret may interact with the alpha-receptors localized in the target neurons (termed interaction "in trans"). In addition, we present evidence in vitro that GFRalpha-1 mediates Ret activation by GDNF in trans. These observations suggest that there are multiple mechanisms regulating the interaction between Ret and the alpha-receptors that mediates the effects of GDNF family trophic factors on the survival and differentiation of cells and on neuron-target interactions in the nervous system.

Mammalian GFRα-4, a Divergent Member of the GFRα Family of Coreceptors for Glial Cell Line-derived Neurotrophic Factor Family Ligands, Is a Receptor for the Neurotrophic Factor Persephin

“…We have indeed found that variant B is probably secreted by transfected cells at higher levels than variant A. The occurrence of soluble GFR␣-4 receptor isoforms could function to present PSP to cRET in trans to cells expressing cRET but no GFR␣-4, as hypothesized for GDNF/GFR␣-1 (25,26).…”

“…However, it has also been shown that GFR␣-1 to GFR␣-3 subunits are able to modulate cRET tyrosine phosphorylation, thus suggesting that GFR␣ and cRET can interact in the absence of ligand (21)(22)(23)(24). Recently, other signaling mechanisms have been proposed, wherein GFR␣ coreceptors function to present GDNF family ligands in trans to cRET-expressing cells (25,26) or wherein ligand-GFR␣ complexes can activate intracellular signaling pathways independently from cRET (27,28). In vitro, GFR␣-1 is the preferred receptor for GDNF, whereas GFR␣-2 preferentially binds NTN (9,13,29).…”

Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

“…GDNF mRNA is highly expressed in the striatum during development (Schaar et al, 1993;Stromberg et al, 1993;Blum and Weickert, 1995;Choi-Lundberg and Bohn, 1995;Golden et al, 1999), and we have shown by quantitative analysis that its highest level of expression is on PND 2 (Cho et al, 2003), during the first phase. The receptor for GDNF, GDNF receptor ␣1 (GFR␣1), and its signaling tyrosine kinase, Ret, are both highly expressed in SNpc during development (Widenfalk et al, 1997;Yu et al, 1998). As expected for a target-derived factor, GDNF can be specifically transported retrograde from striatum to SNpc (Tomac et al, 1995b).…”

“…These results may indicate, for example, that nigrostriatal dopaminergic innervation, unlike mesocortical dopaminergic innervation, is limited by some factor other than, or in addition to, GDNF. One possibility is that striatal GFR␣1, exerting an effect in trans (Yu et al, 1998;Paratcha et al, 2001), becomes limiting in the doubletransgenic animals. Such an effect has been demonstrated in vitro for neurite growth of nodose and sympathetic ganglia grown in the presence of nonlimiting concentrations of GDNF (Ledda et al, 2002).…”

Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

“…Glial cell line-derived neurotrophic factor family of receptors-α (GFRαs) are typically coupled to the receptor tyrosine kinase Ret (1). However, GFRαs are more widely expressed than Ret, and Ret-independent GFL-induced neuronal sensitization has been reported, suggesting that these receptors may signal through additional transmembrane proteins (13)(14)(15)(16).…”