Glial cell line-derived neurotrophic factor receptor-α1 expressed in striatum in trans regulates development and injury response of dopamine neurons of the substantia nigra.
Many of the cellular effects of glial cell line-derived neurotrophic factor are initiated by binding to GNDF family receptor alpha-1 (GFRα1), and mediated by diverse intracellular signaling pathways, most notably through the Ret tyrosine kinase. Ret may be activated by the cell autonomous expression of GFRα1 ('in cis'), or by its non-cell autonomous presence ('in trans'), in either a soluble or immobilized state. GFRα1 is expressed in the striatum, a target of the dopaminergic projection of the substantia nigra. To determine whether post-synaptic expression of GFRα1 in striatum in trans has effects on the development or adult responses to injury of dopamine neurons, we have created transgenic mice in which GFRα1 expression is selectively increased in striatum and other forebrain targets of the dopaminergic projection. Post-synaptic GFRα1 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 GFRα1 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 GFRα1 expression has important effects on the biology of dopamine neurons in vivo.
Department of Neurology, The College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Nikolai
N
Kholodilov
Sang Ryong
SR
Kim
Olga
O
Yarygina
Tatyana
T
Kareva
Jin Whan
JW
Cho
Amy
A
Baohan
Robert E
RE
Burke
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D003342:Corpus Striatum / Q000254:growth & development* / Q000293:injuries* / Q000473:pathology; D004298:Dopamine / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology / Q000502:physiology; D051381:Rats; D013378:Substantia Nigra / Q000254:growth & development* / Q000293:injuries* / Q000473:pathology
C494989:Gfra1 protein, rat; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D004298:Dopamine