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First published online September 2, 2003
doi: 10.1242/10.1242/jcs.00786
Commentary |
1 Institute of Biomedicine, University of Helsinki, PO Box 63 (Haartmaninkatu
8), FIN-00014 and HUCH Laboratory Diagnostics, PO Box 400, Helsinki University
Central Hospital, FIN-00029, Finland
2 Institute of Biotechnology, University of Helsinki, PO Box 56 (Viikinkaari 9),
University of Helsinki, FIN-00014, Finland
* Author for correspondence (e-mail: hannu.sariola{at}helsinki.fi)
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 
(GFR) 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 ß, which activates
the transport of GFR1 to the cell membrane. GDNF can also signal RET
independently through GFR1. Upon ligand binding, GDNF in complex with
GFR1 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 GFR1
complex, which activates Fyn and FAK.
Key words: Glial-cell-line-derived neurotrophic factor, RET receptor tyrosine kinase, Met receptor tyrosine kinase, GDNF family receptor , NCAM, Neuronal survival, Kidney morphogenesis, Spermatogenesis
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