Glial cell line-derived neurotrophic factor receptor-alpha 1 expressed in striatum in trans regulates development and injury response of dopamine neurons of the substantia nigra

P>Many of the cellular effects of glial cell line-derived neurotrophic factor are initiated by binding to GNDF family receptor alpha-1 (GFR alpha 1), and mediated by diverse intracellular signaling pathways, most notably through the Ret tyrosine kinase. Ret may be activated by the cell autonomous expression of GFR alpha 1 ('in cis'), or by its non-cell autonomous presence ('in trans'), in either a soluble or immobilized state. GFR alpha 1 is expressed in the striatum, a target of the dopaminergic projection of the substantia nigra. To determine whether post-synaptic expression of GFR alpha 1 in striatum in trans has effects on the development or adult responses to injury of dopamine neurons, we have created transgenic mice in which GFR alpha 1 expression is selectively increased in striatum and other forebrain targets of the dopaminergic projection. Post-synaptic GFR alpha 1 has profound effects on the development of dopamine neurons, resulting in a 40% increase in their adult number. This morphologic effect was associated with an augmented motor response to amphetamine. In adult mice, post-synaptic GFR alpha 1 expression did not affect neuron survival following neurotoxic lesion, but it did increase the preservation of striatal dopaminergic innervation. We conclude that post-synaptic striatal GFR alpha 1 expression has important effects on the biology of dopamine neurons in vivo.