Ciliary neurotrophic factor may activate mature astrocytes via binding with the leukemia inhibitory factor receptor.
Ciliary neurotrophic factor (CNTF) acts on immature astrocytes that express its trimeric receptor. In contrast, mature astrocytes do not significantly express the specific CNTFalpha receptor subunit, yet they respond to CNTF administration in vivo. Here we show that this controversy may be solved by a shift in astroglial sensitivity to CNTF over time, related to a change in the type of receptor bound by the cytokine on mature astrocytes. A convergent set of results supports the hypothesis that the CNTF effect is due to the illegitimate binding on the leukemia inhibitory factor receptor (LIFR): (i) it requires high concentration of recombinant rat CNTF; (ii) it involves the Jak/Stat and Ras-MAPK pathways; (iii) it is preserved in CNTFRalpha-/- cells; (iv) it is potentiated by soluble CNTFRalpha added to the medium; and (v) it is significantly decreased by a partial antagonist of LIFR. On these bases, we propose a mechanistic model in which, in the adult brain, a CNTF/LIFR interglial system may be modulated by neurons that synthesize CNTFRalpha.
Monville
C
C
INSERM U421, Créteil cedex, 94010, France.
Coulpier
M
M
Conti
L
L
De-Fraja
C
C
Dreyfus
P
P
Fages
C
C
Riche
D
D
Tardy
M
M
Cattaneo
E
E
Peschanski
M
M
D000818:Animals; D001253:Astrocytes / Q000737:chemistry / Q000201:enzymology*; D002454:Cell Differentiation / Q000502:physiology; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology*; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D020801:Receptor, Ciliary Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D018121:Receptors, Cytokine / Q000737:chemistry / Q000378:metabolism*; D053606:Receptors, OSM-LIF; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D020934:Ciliary Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507841:Lifr protein, mouse; C507842:Lifr protein, rat; D020801:Receptor, Ciliary Neurotrophic Factor; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF