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

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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 (GFRα-1 or GFRα-2) and the receptor protein tyrosine kinase Ret. Recently, a third receptor related to GFRα-1 and GFRα-2 has also been isolated and designated GFRα-3. Although much is known about the interaction among GDNF family factors, Ret, and the α-receptors in vitro, it remains unclear about their interactions in vivo. We show here by in situ hybridization that Ret and the α-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 α-receptors exist in vivo. First, Ret may interact with the α-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 α-receptors localized in the target neurons (termed interaction “in trans”). In addition, we present evidence in vitro that GFRα-1 mediates Ret activation by GDNF in trans. These observations suggest that there are multiple mechanisms regulating the interaction between Ret and the α-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.