Enovin, a member of the glial cell-line-derived neurotrophic factor (GDNF)family with growth promoting activity on neuronal cells - Existence and tissue-specific expression of different splice Variants

Glial cell-line-derived neurotrophic factor (GDNF), neutrurin and persephin are neurotrophic factors involved in neuroneal differentiation, developmen t and maintenance. They act on different types of neuroneal cells and signa l through a receptor complex composed of a specific ligand-binding subunit of the GDNF family receptor cu (GFR alpha) family together with a common si gnaling partner, the cRET protein tyrosine kinase. We describe the molecula r cloning, expression, chromosomal localization and functional characteriza tion of enovin, a fourth GDNF family member almost identical to the recentl y described artemin. We show the occurence in most tissues of several diffe rently spliced mRNA variants for enovin, of which only two are able to tran slate into functional enovin protein. Some tissues seem to express only non functional transcripts. These observations may underlie a complex transcrip tional regulation pattern. Enovin mRNA expression is detectable in all adul t and fetal human tissues examined, but expression levels are highest in pe ripheral tissues including prostate. placenta, pancreas, heart and kidney. This tissue distribution pattern is in accordance with that of GFR alpha-3, which here is shown to be the preferred ligand-binding receptor for enovin (K-d = 3.1 nM). The human enovin gene is localized on chromosome 1, region p31.3-p32. In vitro, enovin stimulates neurite outgrowth and counteracts t axol-induced neurotoxicity in staurosporine-differentiated SH-SY5Y human ne uroblastoma cells. The peripheral expression pattern of enovin and its rece ptor together with its effects on neuroneal cells suggest that enovin might be useful for the treatment of neurodegenerative diseases in general and p eripheral neuropathies in particular.