TDAG51 Mediates Negative Signaling Crosstalk Between NGF/p75NTR-Induced Cell Death and GDNF/RET-Promoted Survival in Motor Neuron-Derived Cells

Abstract

GDNF is a potent survival and differentiation factor for motor neurons and other central and peripheral neuronal populations. While the signaling pathways by which GDNF promotes survival/differentiation have been relatively well established, the molecular mechanisms that restrict its biological effects remain unclear. In this study, we show that TDAG51 plays a role in regulating the GDNF-induced PI3K/AKT survival pathway. Our findings demonstrate that treatment of motor neuron-derived MN1 cells with high levels of nerve growth factor (NGF), a treatment that under oxidative conditions promotes p75 neurotrophin receptor (p75NTR)-dependent motor neuron apoptosis, induces TDAG51, which in turn inhibits GDNF/RET-mediated AKT signaling. Moreover, knockdown of Tdag51 potentiates the ability of GDNF to activate AKT and provides protection against NGF-induced p75NTR-dependent cell death in MN1 cells. Mechanistically, short-term GDNF stimulation of MN1 cells expressing high levels of TDAG51 promotes the translocation and recruitment of TDAG51 into detergent-resistant plasma membrane microdomains via a PI3K-dependent mechanism. The NGF/p75NTR signaling-induced increase in TDAG51 levels antagonizes AKT activation triggered by GDNF/RET signaling, likely by interfering with AKT´s interaction with PIP3. Taken together, our results demonstrate that TDAG51 is a key mediator of the balance between NGF-induced p75NTR-promoted apoptotic pathway and GDNF/RET-mediated survival signaling in MN1 neuronal cells.