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The Journal of Neuroscience, November 1, 1999, 19(21):9160-9169
Receptors of the Glial Cell Line-Derived Neurotrophic Factor
Family of Neurotrophic Factors Signal Cell Survival through the
Phosphatidylinositol 3-Kinase Pathway in Spinal Cord
Motoneurons
Rosa M.
Soler,
Xavier
Dolcet,
Mario
Encinas,
Joaquim
Egea,
Jose R.
Bayascas, and
Joan X.
Comella
Grup de Neurobiologia Molecular, Departament de Ciències
Mèdiques Bàsiques, Facultat de Medicina, Universitat de
Lleida, 25198 Lleida, Catalonia, Spain
The members of the glial cell line-derived neurotrophic factor
(GDNF) family of neurotrophic factors (GDNF, neurturin, persephin, and
artemin) are able to promote in vivo and in
vitro survival of different neuronal populations, including
spinal cord motoneurons. These factors signal via multicomponent
receptors that consist of the Ret receptor tyrosine kinase plus a
member of the GDNF family receptor  (GRF) family of
glycosylphosphatidylinositol-linked coreceptors. Activation of the
receptor induces Ret phosphorylation that leads the survival-promoting
effects. Ret phosphorylation causes the activation of several
intracellular pathways, but the biological effects caused by the
activation of each of these pathways are still unknown. In the present
work, we describe the ability of the GDNF family members to promote
chicken motoneuron survival in culture. We show the presence of Ret and
GFR-1, GFR-2, and GFR-4 in chicken motoneurons using in
situ hybridization and reverse transcription-PCR techniques. By
Western blot analysis and kinase assays, we demonstrate the ability of
these factors to induce the phosphatidylinositol 3 kinase (PI 3-kinase)
and the extracellular regulated kinase (ERK)-mitogen-activated protein (MAP) kinase pathways activation. To characterize the involvement of
these pathways in the survival effect, we used the PI 3-kinase inhibitor LY 294002 and the MAP kinase and ERK kinase (MEK)
inhibitor PD 98059. We demonstrate that LY 294002, but not PD 98059, prevents GDNF-, neurturin-, and persephin-induced motoneuron survival, suggesting that PI 3-kinase intracellular pathway is responsible in
mediating the neurotrophic effect.
Key words:
GDNF; persephin; neurturin; artemin; motoneuron; neurotrophic factor; GFR receptors; chicken; intracellular signaling
pathway
Copyright © 1999 Society for Neuroscience 0270-6474/99/19219160-10$05.00/0
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