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

Abstract

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 pathwayGlial cell line-derived neurotrophic factor (GDN F), neurturin (NTN), persephin (PSP), and artemin (ART) are the members of a new family of neurotrophic factors distantly related to the members of the TGF␤ family (Lin et al

Substantia nigra dopaminergic neurons and striatal interneurons are engaged in three parallel but interdependent postnatal neurotrophic circuits

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Bcl-2 Is a Key Factor for Cardiac Fibroblast Resistance to Programmed Cell Death

“…PCR products from cycles 25, 30, and 35 from retrotranscribed samples and control samples, where the RT reaction was omitted, were migrated in 2% agarose gels and visualized by ethidium bromide staining. Amplification of ribosomal gene L27 was carried out as the control for cDNA input in the amplification reaction (32).…”

The Canonical Nuclear Factor-κB Pathway Regulates Cell Survival in a Developmental Model of Spinal Cord Motoneurons

“…The large variety of neurotrophic molecules that can support MN survival in vivo and in vitro indicates that developing and postnatal MNs depend on a cooperation of these molecules that is so far not fully understood (Oppenheim, 1996;Holtmann et al, 2005). NTFs promoting MN survival in vivo and in vitro belong to different gene families and activate several signaling pathways (Soler et al, 1999;Dolcet et al, 2001). To maintain MNs alive in culture, we (Gou-Fabregas et al, 2009) and others (Arce et al, 1999) use a cocktail of NTFs to achieve the maximal cell survival rates.…”