Abstract
Glial-cell-line-derived neurotrophic factor (GDNF) was originally identified as a survival factor for midbrain dopaminergic neurons. GDNF and related ligands, neurturin (NRTN), artemin (ARTN) and persephin (PSPN), maintain several neuronal populations in the central nervous systems, including midbrain dopamine neurons and motoneurons. In addition, GDNF, NRTN and ARTN support the survival and regulate the differentiation of many peripheral neurons, including sympathetic, parasympathetic, sensory and enteric neurons. GDNF has further critical roles outside the nervous system in the regulation of kidney morphogenesis and spermatogenesis. GDNF family ligands bind to specific GDNF family receptor alpha (GFRalpha) proteins, all of which form receptor complexes and signal through the RET receptor tyrosine kinase. The biology of GDNF signalling is much more complex than originally assumed. The neurotrophic effect of GDNF, except in motoneurons, requires the presence of transforming growth factor beta, which activates the transport of GFRalpha1 to the cell membrane. GDNF can also signal RET independently through GFR1alpha. Upon ligand binding, GDNF in complex with GFRalpha1 may interact with heparan sulphate glycosaminoglycans to activate the Met receptor tyrosine kinase through cytoplasmic Src-family kinases. GDNF family ligands also signal through the neural cell adhesion molecule NCAM. In cells lacking RET, GDNF binds with high affinity to the NCAM and GFRalpha1 complex, which activates Fyn and FAK.
Highlights
Neurotrophic factors regulate many critical aspects of the ontogeny of neurons, such as the number of neurons in a given population, neurite branching and synaptogenesis, adult synaptic plasticity and maturation of electrophysiological properties
glial-cell-line-derived neurotrophic factor (GDNF) was purified and characterized in 1993 as a growth factor promoting the survival of the embryonic dopaminergic neurons of the midbrain, i.e. those neurons that degenerate in Parkinson disease (Lin et al, 1993)
In MDCK cells expressing GFRα1 but not RET, GDNF stimulates branching but not chemotactic migration. Both branching and chemotaxis are promoted by GDNF in cells co-expressing RET and GFRα1, which mimics the effects of hepatocyte growth factor (HGF) signalling through the Met receptor tyrosine kinase in wild-type MDCK cells
Summary
Glial-cell-line-derived neurotrophic factor (GDNF) was originally identified as a survival factor for midbrain dopaminergic neurons. GDNF and related ligands, neurturin (NRTN), artemin (ARTN) and persephin (PSPN), maintain several neuronal populations in the central nervous systems, including midbrain dopamine neurons and motoneurons. GDNF, NRTN and ARTN support the survival and regulate the differentiation of many peripheral neurons, including sympathetic, parasympathetic, sensory and enteric neurons. GDNF in complex with GFRα1 may interact with heparan sulphate glycosaminoglycans to activate the Met receptor tyrosine kinase through cytoplasmic Src-family kinases. GDNF family ligands signal through the neural cell adhesion molecule NCAM. In cells lacking RET, GDNF binds with high affinity to the NCAM and GFRα1 complex, which activates Fyn and FAK
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