GFR alpha 1 Is Required for Development of Distinct Subpopulations of Motoneuron

Glial cell-line derived neurotrophic factor (GDNF) and its relative neurturin (NTN) are potent trophic factors for motoneurons. They exert their biological effects by activating the RET tyrosine kinase in the presence of a glycosyl-phosphatidylinositol-linked co-receptor, either GFR alpha 1 or GFR a...

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Published in:The Journal of neuroscience 2000-07, Vol.20 (13), p.4992-5000
Main Authors: Garces, A, Haase, G, Airaksinen, MS, Livet, J, Filippi, P, DeLapeyriere, O
Format: Article
Language:English
Subjects:
GFR protein
neurturin
Ret protein
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Summary:Glial cell-line derived neurotrophic factor (GDNF) and its relative neurturin (NTN) are potent trophic factors for motoneurons. They exert their biological effects by activating the RET tyrosine kinase in the presence of a glycosyl-phosphatidylinositol-linked co-receptor, either GFR alpha 1 or GFR alpha 2. By whole-mount in situ hybridization on embryonic mouse spinal cord, we demonstrate that whereas Ret is expressed by nearly all motoneurons, Gfra1 and Gfra2 exhibit complex and distinct patterns of expression. Most motoneurons purified from Gfra1 null mutant mice had lost their responsiveness to both GDNF and NTN. However, a minority of them ( similar to 25%) retained their ability to respond to both factors, perhaps because they express GFR alpha 2. Surprisingly, Gfra2 super(-/-) motoneurons showed normal survival responses to both GDNF and NTN. Thus, GFR alpha 1, but not GFR alpha 2, is absolutely required for the survival response of a majority of motoneurons to both GDNF and NTN. In accordance with the phenotype of the mutant motoneurons observed in culture we found the loss of distinct groups of motoneurons, identified by several markers, in the Gfra1 super(-/-) spinal cords but no gross defects in the Gfra2 super(-/-) mutant. During their natural programmed cell death period, motoneurons in the Gfra1 super(-/-) mutant mice undertook increased apoptosis. Taken together these findings support the existence of subpopulations of motoneuron with different trophic requirements, some of them being dependent on the GDNF family.
ISSN:0270-6474