Regulation of glial cell line-derived neurotrophic factor responsiveness in developing rat sympathetic neurons by retinoic acid and bone morphogenetic protein-2.
There are several lines of evidence suggesting that, in addition to neurotrophins, member(s) of glial cell line-derived neurotrophic factor (GDNF) family play important roles in the development of sympathetic neurons. However, the mechanism regulating the responsiveness of the neurons to GDNF family members is not known. Previously, we reported on the cooperative roles of bone morphogenetic protein-2 (BMP2) and retinoic acid (RA) in the enhancement of neurotrophin-3 (NT3) responsiveness in cultured sympathetic neurons dissociated from perinatal rat superior cervical ganglia (SCG). In the present study, we further examined the effects of BMP2 and RA on the regulation of the responsiveness of SCG neurons to GDNF family members. Consequently, we found that RA alone induced the responsiveness of SCG neurons specifically to GDNF by upregulating the ligand-specifying receptor for GDNF (GFRalpha-1) at both the mRNA and protein levels. The expression levels of mRNAs for other ligand-specifying receptors for GDNF family (GFRalpha-2 and GFRalpha-3) were unaffected by RA. Although the upregulation of signal-transducing receptor Ret by the RA treatment was rather small, this treatment significantly increased the efficacy of tyrosine phosphorylation of Ret by GDNF. Experiments using synthetic retinoids suggested that RA acts through alpha-type of nuclear retinoic acid receptor to exert the induction of GDNF responsiveness. On the other hand, BMP2, which had no significant effect by itself on the GDNF responsiveness, promoted the action of RA to upregulate GFRalpha-1 and enhance the GDNF responsiveness. These results indicate that RA and BMP2 play important roles in the induction of GDNF responsiveness, as well as NT3 responsiveness, of developing SCG neurons.
Thang
S H
SH
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku, Sapporo 060-0812, Japan.
Kobayashi
M
M
Matsuoka
I
I
D000320:Adrenergic Fibers / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D004347:Drug Interactions; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D051379:Mice; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016211:Transforming Growth Factor alpha / Q000187:drug effects* / Q000378:metabolism; D016212:Transforming Growth Factor beta; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation
C525719:Bmp2 protein, mouse; C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; C494994:Gfra3 protein, mouse; C494995:Gfra3 protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; D014212:Tretinoin