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First published online September 2, 2003
doi: 10.1242/10.1242/jcs.00786

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Novel functions and signalling pathways for GDNF

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

View larger version (30K): [in a new window]   Fig. 1. GDNF-family ligand interaction with their receptors. (A) A dimer of GDNF brings together two molecules of GFR1. This complex dimerizes two molecules of Ret leading to transphophorylation of their tyrosine kinase domains. (B) All GFLs activate RET tyrosine kinase via different GFR receptors. Solid arrows indicate the preferred functional ligand-receptor interactions, whereas dotted arrows indicate putative crosstalk. GFR proteins are attached to the plasma membrane through a GPI-anchor and consist of three (GFR4 has only two) globular cysteine-rich domains joined together by adapter sequences. Ca2+ ions bound to one of the four extracellular cadherin-like domains of RET are needed for its activation by GFLs.

View larger version (30K): [in a new window]   Fig. 2. Non-Ret signalling for GDNF and GFR-independent signalling for RET. (A) GDNF promotes phosphorylation of Met. Its activation is indirect and is mediated by Src-type kinases. Various types of evidence suggest that GDNF is locally concentrated by heparan sulphate proteoglycans, such as syndecan. By contrast, RET is phosphorylated, by an unknown mechanism, through the activation of TrkA. Heparan sulphate proteoglycans may modulate GDNF signalling by local concentration of the ligand. (B) NCAM is an alternative signalling receptor for GFLs. It interacts with a GDNF-GFR dimer leading to activation of Fyn, a Src-like kinase, for instance. It is not known whether Fyn activates Met in NCAM-mediated GDNF signalling.

View larger version (38K): [in a new window]   Fig. 3. GDNF regulates kidney development. GDNF (red) is expressed by the metanephric mesenchyme, and RET (green) by the Wolffian duct, from which the ureteric budding is promoted by GDNF. When the tip of the bud has induced two subsets of mesenchymal cells for epithelial differentiation, these cells strongly upregulate GDNF. This leads to formation of a double-gradient of GDNF around the ureteric tip and its branching.

View larger version (26K): [in a new window]   Fig. 4. Control of spermatogonial stem cell differentiation and self-renewal by GDNF dosage. GDNF is expressed by the Sertoli cells in the seminiferous tubules. These cells control sperm differentiation in a paracrine manner. When the GDNF level is low, the spermatogenic stem cells enter the differentiation pathway. When its level is high, the stem cells only self-renew and are unable to differentiate. In transgenic mice with loss- and gain-of-function of GDNF, both conditions lead to disturbed spermatogenesis.