GDNF-Induced Expression of Tyrosine Hydroxylase

Glial cell line-derived neurotrophic factor (GDNF) was first identified as a protein with specific neurotrophic activity affecting the dopaminergic neurons of the substantia nigra.1 Since then, several studies have shown that GDNF plays an important role in mediating the survival of dopaminergic neurons.2, 3 The signal transduction pathway through which GDNF exerts this effect is thought to be GFRα-1 and Ret-dependent,4 and to involve MAP kinase and PI-3 kinase.5, 6 The tyrosine hydroxylase (TH) gene is considered to be a likely target for GDNF signaling, since intrastriatal injection of GDNF enhances nigral TH activity and dopamine content (in postnatal rats10). First discovered by Nagatsu et al. in 1964,7 TH catalyzes the rate-limiting step in catecholamine biosynthesis and since then has been the subject of numerous studies investigating the regulation of its expression and activity.8,9 The principle processes controlling the number and intrinsic catalytic activity of this enzyme include: (i) modulation of its transcription; (ii) modulation of its translation; (iii) mRNA splicing, (iv) modulation of mRNA stability; (v) phosphorylation; and (vi) feedback inhibition. Here we investigate in more detail the relationship between GDNF stimulation and TH expression.