Regulation of Glial Cell Line-Derived Neurotrophic Factor Responsiveness in Developing Rat Sympathetic Neurons by Retinoic Acid and Bone Morphogenetic Protein-2

Abstract

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 (GFR␣-1) at both the mRNA and protein levels. The expression levels of mRNAs for other ligand-specifying receptors for GDNF family (GFR␣-2 and GFR␣-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 ␣-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 GFR␣-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.

Glial Cell–Derived Cytokines Attenuate the Breakdown of Vascular Integrity in Diabetic Retinopathy

“…1H), partially supporting the differential sensitivity of retinoic acids on astrocytes and the idea that RAR␣ stimulants preferentially acted on glial cells to upregulate GDNF expression. This observation was consistent with the published result showing that RAR␣ agonists were, at least in part, important regulators of GDNF expression (17). On the other hand, treatment with RAR␣ stimulants downregulated VEGF expression (Fig.…”

“…A previous study has shown that ATRA can differentiate pluripotent embryonal carcinoma cells into neuronal and glial tissues and that it plays an important role in the induction of GDNF responsiveness in these cells (17). This evidence prompted us to investigate whether retinoic acids such as ATRA act on glial cells and, consequently, whether they have any effects on endothelial cells in the BRB.…”

Developmental changes in neurite outgrowth responses of dorsal root and sympathetic ganglia to GDNF, neurturin, and artemin

“…The phenotype of the nervous system of mice lacking GFLs or their receptors indicated that (1) GDNF plays an essential role in the development of the enteric nervous system and may also play a role in the development of sympathetic and sensory neurons (Moore et al, 1996;Pichel et al, 1996;Sanchez et al, 1996;Cacalano et al, 1998;Enomoto et al, 1998;Tomac et al, 2000); (2) neurturin plays an important role in the development of subpopulations of parasympathetic, sensory, and enteric neurons (Heuckeroth et al, 1999;Rossi et al, 1999;Hiltunen et al, 2000); and (3) artemin plays a role in the development of sympathetic ganglia (Nishino et al, 1999;Honma et al, 2002). In vitro studies of peripheral neurons have shown that GDNF promotes the proliferation of enteric neural precursors and the survival and differentiation of enteric, sympathetic, parasympathetic, and sensory neurons (Trupp et al, 1995;Chalazonitis et al, 1998;Hearn et al, 1998;Heuckeroth et al, 1998;Forgie et al, 1999;Taraviras et al, 1999;Thang et al, 2000;Worley et al, 2000); neurturin promotes the survival and differentiation of sympathetic, parasympathetic, enteric, and sensory neurons (Kotzbauer et al, 1996;Matheson et al, 1997;Milbrandt et al, 1998;Forgie et al, 1999;Taraviras et al, 1999;Thang et al, 2000); and artemin supports the survival of sensory and sympathetic neurons Andres et al, 2001).…”

Inflammation and Angiogenesis in Diabetic Retinopathy

“…The phenotypic transformation of glial cells mediated by RARa is sufficient for significant reductions of vascular leakage in the diabetic retina, suggesting that RARa antagonizes the loss of tight junction integrity induced by diabetes. These findings reveal that glial cellderived cytokines such as GDNF and VEGF regulate BRB function, implying that the glial cell can be a possible therapeutic target in diabetic retinopathy 204 .…”