TY - JOUR
AU - Saarma, Mart
AB - 


 Four different glial cell line-derived neurotrophic factor (GDNF)-family ligand (GFL)– receptor (GFRα) binding pairs exist, and they all signal through the transmembrane RET receptor tyrosine kinase. 


 Recruitment of RET to lipid rafts, induced by GFL binding to glycolipid-anchored GFRα receptors, is necessary for efficient downstream signalling. RET stimulation by soluble or matrix-bound GFL–GFRα complex activates distinct signalling pathways outside the rafts, and leads to sustained signalling inside the rafts. 


 Regulation of GFL and soluble GFRα receptor production, their interactions with the extracellular matrix, as well as internalization and degradation of the GFL–GFRα–RET receptor complex, are poorly understood. 


 GDNF acts in synergy with other growth factors, including transforming growth factor-β, but the mechanisms are unclear. Nerve growth factor (NGF) can activate RET by its tyrosine kinase receptor TrkA through an unknown intracellular pathway, independently of GFLs and GFRα receptors. GDNF can activate Src-family kinases through GFRα1 and an unknown transmembrane linker protein in a RET-independent manner. 


 GFLs might regulate the expression of their cognate co-receptors. Regulation of neurotransmitter release by GDNF implies a role in synaptic plasticity. 


 Sympathetic precursors require artemin, which is produced locally or by intermediate target cells, primarily for migration, but also for proliferation and early differentiation. Similarly, parasympathetic and enteric precursors require GDNF. 


 During target innervation, sympathetic neurons become dependent on NGF rather than artemin for their survival. By contrast, parasympathetic neurons switch their requirements from GDNF to target-derived neurturin for terminal innervation and the maintenance of cell size. 


 In somatic sensory neurons, GFLs regulate soma size, target innervation and nociception, but are not required for survival in vivo. 


 A subpopulation of motor neurons requires GDNF, which is produced by Schwann cells, to avoid programmed cell death. GDNF- but not brain-derived neurotrophic factor-mediated protection of injured motor neurons requires inhibitor of apoptosis proteins. So, trophic signalling differs between neurotrophins and GFLs. 


 Apart from promoting neuronal maintenance and regeneration, GFL-like drugs might be useful in the treatment of disorders such as neuropathic pain and addiction.



TI - The GDNF family: Signalling, biological functions and therapeutic value
JF - Nature Reviews Neuroscience
DO - 10.1038/nrn812
DA - 2002-05-01
UR - https://www.deepdyve.com/lp/springer-journals/the-gdnf-family-signalling-biological-functions-and-therapeutic-value-CUXu3AgQBI
SP - 383
EP - 394
VL - 3
IS - 5
DP - DeepDyve
ER -