Conditional, genetic disruption of ciliary neurotrophic factor receptors reveals a role in adult motor neuron survival.
Indirect evidence suggests that endogenous ciliary neurotrophic factor (CNTF) receptor signaling can promote motor neuron (MN) survival in the adult. If so, proper targeting of this signaling may selectively counteract the effects of adult MN diseases. However, direct evidence for CNTF receptor involvement in adult MN survival is lacking, presumably because the unconditional blockade of the mouse CNTF receptor in vivo [through genetic disruption of the essential CNTF receptor alpha (CNTFRalpha) gene] leads to uniform perinatal death of the mice. To overcome this limitation, we have developed a method to selectively disrupt CNTF receptor function in a targeted subset of adult MNs that are not required for survival. A 'floxed CNTFRalpha' mouse line was generated and characterized. In addition, an adeno-associated virus (AAV) vector that drives Cre recombinase (Cre) expression was constructed and shown, with reporter mouse lines, to selectively excise floxed genes in facial MNs following its stereotaxic injection into the facial motor nucleus. Adult floxed CNTFRalpha mice were then injected with the AAV-Cre vector to excise the CNTFRalpha gene in the targeted MNs. The resulting data indicate that adult CNTF receptor signaling, likely by the MNs themselves, can play an essential role in MN survival. The data further indicate that this role is independent of any developmental contributions CNTF receptor signaling makes to MN survival or function.
Lee
Nancy
N
Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH 45267-0576, USA.
Robitz
Rachel
R
Zurbrugg
Rebekah J
RJ
Karpman
Adam M
AM
Mahler
Ashley M
AM
Cronier
Samantha A
SA
Vesey
Rachel
R
Spearry
Rachel P
RP
Zolotukhin
Sergei
S
Maclennan
A John
AJ
D000367:Age Factors; D000818:Animals; D002470:Cell Survival / Q000235:genetics; D002490:Central Nervous System / Q000378:metabolism*; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005154:Facial Nerve / Q000166:cytology / Q000378:metabolism; D018390:Gene Targeting / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D019426:Integrases / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism*; D020801:Receptor, Ciliary Neurotrophic Factor / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection
D020934:Ciliary Neurotrophic Factor; D020801:Receptor, Ciliary Neurotrophic Factor; C045073:Cre recombinase; D019426:Integrases