EXPRESSION OF GDNF FAMILY RECEPTOR COMPONENTS DURING DEVELOPMENT - IMPLICATIONS IN THE MECHANISMS OF INTERACTION

Glial cell line-derived neurotrophic factor (GDNF) and a related facto r, neurturin, promote survival of diverse groups of neurons. Both GDNF and neurturin signal via a two-component receptor complex that consis ts of a ligand-binding GDNF family receptor (GFR alpha-1 or GFR alpha- 2) and the receptor protein tyrosine kinase Ret. Recently, a third rec eptor related to GFR alpha-1 and GFR alpha-2 has also been isolated an d designated GFR alpha-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 s itu hybridization that Ret and the alpha-receptors may be colocalized in the same tissues or expressed separately in projecting and target t issues, respectively, indicating that two distinct modes of interactio n between Ret and the alpha-receptors exist in vivo. First, Ret may in teract with the alpha-receptors expressed in the same cells (termed in teraction ''in cis'') in many tissues and cell populations that respon d to GDNF and/or neurturin, such as the substantia nigra, dorsal root ganglia, spinal cord motoneurons, kidney, and intestine. Second, Ret m ay interact with the alpha-receptors localized in the target neurons ( termed interaction ''in trans''). In addition, we present evidence in vitro that GFR alpha-1 mediates Ret activation by GDNF in trans. These observations suggest that there are multiple mechanisms regulating th e interaction between Ret and the alpha-receptors that mediates the ef fects of GDNF family trophic factors on the survival and differentiati on of cells and on neuron-target interactions in the nervous system.