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The Journal of Neuroscience, July 1, 2000, 20(13):4992-5000
GFR 1 Is Required for Development of Distinct
Subpopulations of Motoneuron
A.
Garcès1,
G.
Haase1,
M. S.
Airaksinen2,
J.
Livet1,
P.
Filippi1, and
O.
deLapeyrière1
1 Institut National de la Santé et de la
Recherche Médicale (INSERM) U.382, Developmental Biology
Institute of Marseille (Centre National de la Recherche
Scientifique-INSERM-Université de la Méditerranée, AP
de Marseille), Campus de Luminy, 13288 Marseille Cedex 09, France, and
2 Institute of Biotechnology, Viikki Biocenter, University
of Helsinki, Helsinki FIN-00014, Finland
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 1 or GFR2. 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
(~25%) retained their ability to respond to both factors, perhaps
because they express GFR2. Surprisingly,
Gfra2 /
motoneurons showed normal survival responses to both GDNF and NTN.
Thus, GFR1, but not GFR2, 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/ spinal
cords but no gross defects in the
Gfra2/ mutant.
During their natural programmed cell death period, motoneurons in the
Gfra1/ 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.
Key words:
motoneuron subpopulations; motoneuron survival; neurotrophic factors; GDNF; NTN; Ret; Gfra1; Gfra2; in situ
hybridization; mutant mice
Copyright © 2000 Society for Neuroscience 0270-6474/00/20134992-09$05.00/0
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