ReviewThe GDNF family ligands and receptors — implications for neural development
Introduction
Since the discovery of nerve growth factor (NGF) and the establishment of its ability to support neuronal survival 1, 2, 3, extensive efforts have been made to identify additional neurotrophic factors that can influence neurons in primary culture, during normal development, or in experimental models of neuronal injury. This work has resulted in the identification of a large and diverse group of proteins that are capable of promoting neuronal survival in various experimental paradigms. Glial cell line derived neurotrophic factor (GDNF) was initially identified as a factor secreted from a glioma cell line capable of supporting embryonic ventral midbrain neuron survival in culture [4]. Our knowledge of the in vitro activities of GDNF expanded rapidly after its discovery to now include survival promotion of additional central neurons (including spinal motor neurons) and at least a subpopulation of all peripheral ganglia yet examined 5, 6, 7, 8, 9••. The discovery of neurturin (NRTN) three years later, which is ∼44% identical to GDNF, established the existence of the GDNF family ligands (GFLs) [8]. Furthermore, shortly after the discovery of NRTN, both GDNF and NRTN were found to signal through a multicomponent receptor system comprising a high-affinity ligand-binding co-receptor GFRα (GDNF family receptor α-component) and the RET receptor tyrosine kinase 10, 11, 12, 13, 14.
This review briefly describes the recent expansion of the GFLs to include two additional members, persephin (PSPN) and artemin (ARTN), and summarizes the current understanding of ligand–receptor interactions between the four GFLs and GFRα co-receptors. Furthermore, mice with null mutations in the genes encoding GDNF, NRTN and several GDNF family receptors (GFRα1, GFRα2 and GFRα3) have recently provided insight into the critical importance of the GFLs during development, particularly in the peripheral nervous system and in kidney organogenesis. Several excellent reviews of the literature describing the structural biology and therapeutic prospects of the GFLs 15•, 16, 17• and the oncogenic role of RET mutations in multiple endocrine neoplasia type 2 (MEN2) can be found elsewhere 18, 19, 20.
Section snippets
Expansion of the GDNF family
A schematic representation of ligand–receptor interactions of the GFLs characterized by in vitro studies is shown in Figure 1. Shortly after the discovery of the second GFL (NRTN), homology-based PCR screening was used to identify PSPN, and shortly thereafter database searching was used to identify ARTN. As mentioned above, the GFLs signal through a multicomponent receptor complex comprising the RET tyrosine kinase and a high-affinity ligand-binding component (of which there are now
The GFLs are critical trophic factors for developing enteric, sympathetic and parasympathetic neurons
Although it was not known at the time, the study of RET−/− mice was the first analysis of the function of the GFLs in neurodevelopment. Given the current evidence that RET is a common signaling component for all of the GFLs, mice lacking RET should represent a pan-GFL knockout. However, many aspects of the RET−/− phenotype remain to be explored. As mentioned above, these mice die shortly after birth due to lack of kidneys and enteric neurons distal to the stomach [29]. The critical role of RET
Parallels and intersections in the developmental roles of the NGF and the GDNF families
Analysis of knockout mice has revealed extensive parallels in the mechanisms by which the NGF family and GDNF families influence neurodevelopment. First, while receptors for both families are present on central neurons and they can both potently influence central neurons in vitro, they appear to not be critical (at least individually) for the survival of CNS neurons during development. This adds further support to the suggestion that CNS neurons may derive redundant trophic support from many
Conclusions
The recent addition of PSPN and ARTN to the GDNF family ligands, along with confirmation from gene knockout studies of the importance of GDNF and NRTN in neurodevelopment, has established the GFLs as a second family of neurotrophic factors (the other being the NGF family) where different members influence distinct events and support the survival of distinct classes of peripheral neurons during development. While there is some in vitro cross-talk between the different GFLs and GFRαs, the
Acknowledgements
We thank all members of the Milbrandt and Johnson labs for invaluable discussions regarding the ideas and issues presented here. The authors are supported by National Institutes of Health grants R01 AG13729 and R01 AG13730.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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