Cellular and Molecular Neurobiology
Author: Fernando Federicci | Email: fer.federicci@gmail.com
Fernando Federicci1°2°, Fernanda Ledda2°, Gustavo Paratcha1°
1° Laboratorio de Neurociencia Molecular y Celular- Instituto de Biologia Celular y Neurociencias “Prof E. DeRobertis”- UBA. Buenos Aires, Argentina
2° Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires, Buenos Aires, Argentina.
GDNF is a potent survival factor for different neuronal populations including spinal cord motor neurons. However, while the signaling pathways by which GDNF promotes survival has been relatively well established, the molecular mechanisms that restrict the biological effects of this neurotrophic factor remain unknown. Short-term GDNF stimulation of the motoneuron-derived MN1 cells promotes the localization and recruitment of TDAG51 into detergent-resistant plasma membrane microdomains through a PI3K-dependent mechanism, indicating that TDAG51 could regulate proximal downstream signaling events triggered by GDNF and its receptor Ret. In line with this finding, gain and loss of function assays show that TDAG51 has the ability inhibit PI3K/AKT, but not ERK1/2/MAPK pathway activation in response to GDNF.
Interestingly, our findings also demonstrate that stimulation of MN1 cells with NGF, a treatment that promotes p75NTR-dependent motor neuron apoptosis, induces TDAG51 to suppress GDNF/RET-mediated AKT signaling. Knockdown of Tdag51 restored the ability of GDNF to activate AKT and protect MN1 cells from NGF-induced p75NTR-dependent cell death. Taken together, our results demonstrate that TDAG51 is a key mediator of the balance between NGF-induced p75NTR-promoted apoptotic signaling and GDNF/RET-mediated survival signaling in MN1 neuronal cells.