In vivo localization and characterization of functional ciliary neurotrophic factor receptors which utilize JAK-STAT signaling.
The ciliary neurotrophic factor receptor is critically involved in embryonic motor neuron development. Postnatally, it may contribute to neuronal maintenance and regeneration. In addition, pharmacological stimulation of the receptor may slow the progression of several neurodegenerative disorders. The widespread nervous system expression of ciliary neurotrophic factor receptor components and the effects of low ciliary neurotrophic factor concentrations on a wide variety of cells in culture combine to suggest that functional ciliary neurotrophic factor receptors are expressed by many classes of neurons in vivo. However, the in vivo signaling properties and distribution of functional ciliary neurotrophic factor receptors have not been directly determined. We developed a novel in vivo assay of functional ciliary neurotrophic factor receptors which revealed that, in the adult nervous system, cranial and spinal motor neurons are very sensitive to ciliary neurotrophic factor and display a rapid, robust increase in phospho-STAT3 in their dendrites, cell bodies and nuclei, which is specifically blocked by the ciliary neurotrophic factor receptor antagonist, AADH-CNTF. In distinct contrast, several other classes of ciliary neurotrophic factor receptor expressing neurons fail to increase phospho-STAT3 levels following ciliary neurotrophic factor treatment, even when ciliary neurotrophic factor is applied at high concentrations. Leukemia inhibitory factor and epidermal growth factor elicit the same cell-type-dependent pattern of phospho-STAT3 increases. Responsive and non-responsive neurons express comparable levels of STAT3.Therefore, in vivo ciliary neurotrophic factor receptor-initiated STAT3 signal transduction is regulated in a very cell-type-dependent manner. The present data suggest that at least some of this regulation occurs at the STAT3 tyrosine phosphorylation step. These unexpected results also suggest that other forms of receptor-initiated STAT3 signal transduction may be similarly regulated.
MacLennan
A J
AJ
Department of Neuroscience, University of Florida College of Medicine, University of Florida Brain Institute, Gainesville, FL 32610-0244, USA. maclen@nersp.nerdc.ufl.edu
Neitzel
K L
KL
Devlin
B K
BK
Garcia
J
J
Hauptman
G A
GA
Gloaguen
I
I
Di Marco
A
A
Laufer
R
R
Lee
N
N
D000595:Amino Acid Sequence; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005154:Facial Nerve / Q000166:cytology; D006131:Growth Inhibitors / Q000494:pharmacology; D015850:Interleukin-6; D053613:Janus Kinase 1; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000737:chemistry* / Q000201:enzymology*; D016297:Mutagenesis, Site-Directed; D020933:Neurotrophin 3 / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020801:Receptor, Ciliary Neurotrophic Factor / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology; D015534:Trans-Activators / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D020933:Neurotrophin 3; D020801:Receptor, Ciliary Neurotrophic Factor; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; C507906:Jak1 protein, rat; D053613:Janus Kinase 1