Retinoic acid negatively regulates GDNF and neurturin receptor expression and responsiveness in embryonic chicken sympathetic neurons

Neurotrophins and members of the GDNF family influence the generation, differentiation and survival of sympathetic neurons during development. Neurotrophin receptor expression and responsiveness has previously been shown to be regulated by all-trans retinoic acid (RA) in embryonic chicken sympathetic neurons. To determine if RA also regulates responsiveness to GDNF family members and expression of their receptors, we studied the effect of treating cultures of these neurons at a stage when they survive in response to GDNF and neurturin. RA caused a dose-dependent decrease in the survival response to both GDNF and neurturin. Transcripts for the ligand-specifying receptors for GDNF and neurturin, GFRα-1 and GFRα-2, as well as the common signal transducing receptor Ret were all down-regulated by RA treatment in a dose-dependent manner. Transcripts for all three retinoic acid receptors RaRα, RaRβ and RaRγ as well as the enzymes involved in RA synthesis, Adh-1 and RALDH-2, RALDH-3, were present in both sympathetic targets and neurons. Studies with retinoic acid receptor agonists and antagonists revealed that the effects of RA on receptor expression were mediated mainly by RaRα. These findings implicate RA in regulating the actions of members of the GDNF family on developing sympathetic neurons.