GFR alpha 1 is required for development of distinct subpopulations of motoneuron

Glial cell-line derived neurotrophic factor (GDNF) and its relative neurtur in (NTN) are potent trophic factors for motoneurons. They exert their biolo gical effects by activating the RET tyrosine kinase in the presence of a gl ycosyl-phosphatidylinositol-linked co-receptor, either GFR alpha 1 or GFR a lpha 2. By whole-mount in situ hybridization on embryonic mouse spinal cord , we demonstrate that whereas Ret is expressed by nearly all motoneurons, G fra1 and Gfra2 exhibit complex and distinct patterns of expression. Most mo toneurons purified from Gfra1 null mutant mice had lost their responsivenes s to both GDNF and NTN. However, a minority of them (similar to 25%) retain ed their ability to respond to both factors, perhaps because they express G FR alpha 2. Surprisingly, Gfra2(-/-) motoneurons showed normal survival res ponses to both GDNF and NTN. Thus, GFRa1, but not GFR alpha 2, is absolutel y required for the survival response of a majority of motoneurons to both G DNF and NTN. In accordance with the phenotype of the mutant motoneurons obs erved in culture we found the loss of distinct groups of motoneurons, ident ified by several markers, in the Gfra1(-/-) spinal cords but no gross defec ts in the Gfra2(-/-) mutant. During their natural programmed cell death per iod, motoneurons in the Gfra1(-/-) mutant mice undertook increased apoptosi s. Taken together these findings support the existence of subpopulations of motoneuron with different trophic requirements, some of them being depende nt on the GDNF family.