Vitamin D regulation of GDNF/Ret signaling in dopaminergic neurons

Abstract

1,25(OH)2D3 (vitamin D) appears essential for the normal development of dopaminergic neurons. Vitamin D affects dopamine synthesis and metabolism as well as expression of glial cell line-derived neurotrophic factor (GDNF),which is crucial for the survival of dopaminergic neurons.We investigated the role of vitaminDon GDNF and its receptors protooncogene tyrosine-protein kinase receptor Ret (C-Ret) and GDNF family receptor alpha 1 (GFRa1) signaling. To this end,we used a developmental vitaminD-deficient rat model and SH-SY5Y cells transfectedwith vitaminDreceptor (VDR). The absence of vitaminDligand in gestation reduces C-Ret expression, but not GDNF and GFRa1, in embryo forebrains. Overexpression of VDR in SH-SY5Y in the absence of ligand (mimicking in vivo developmental vitamin D deficiency) also suppressed C-Ret mRNA levels. In the presence of vitamin D, C-Ret mRNA and protein expression were increased. The chromatin immunoprecipitation results suggested that C-Ret is directly regulated by vitamin D via VDR. GDNF was also increased by vitamin D in these cells. Our small interfering RNA studies showed that knocking down VDR leads to an increase in C-Ret in the absence of ligand. Finally, we confirmed the inverse relationship between GFRa1 and C-Ret, as knocking down C-Ret led to increases in GFRa1 expression. These data extend our knowledge of the diverse and important roles played by vitamin D in dopamine physiology.-Pertile, R. A. N., Cui, X., Hammond, L., Eyles,D. W. Vitamin D regulation of GDNF/Ret signaling in dopaminergic neurons. FASEB J. 32, 819-828 (2018). www.fasebj.org.