Concerted interaction of TGF-ß and GDNF mediates neuronal differentiation.

ABSTRACT

The glial cell-line derived neurotrophic factor (GDNF) is crucial for ureteric bud morphogenesis, spermatogenesis, and development of the enteric nervous system and is a potent survival factor for various neuronal populations. However, the impact of GDNF, at least on cell survival, was found to depend strongly on the presence of transforming growth factor ß (TGF-ß). In this study, we investigate the role of TGF-ß in GDNF-induced neuronal differentiation. In a cell culture paradigm of N2aGT cells (neuroblastoma cell line), we show that TGF-ß signaling localizes the GDNF ligand-binding receptor GFRa1 to the cell surface, which is a known mechanism by which TGF-ß is able to facilitate GDNF signaling. TGF-ß-mediated GDNF signaling slightly elevated the phosphorylation state of Ret, the canonical coreceptor for the GPI-linked (glycosyl-phosphatidylinositol) GFRa1. On the basis of morphological as well as immunocytological data, we finally show that GDNF-mediated neuronal differentiation is intensified when GDNF and TGF-ß act in concert.