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 embryoni c motor neuron development. Postnatally, it may contribute to neuronal main tenance and regeneration. In addition, pharmacological stimulation of the r eceptor may slow the progression of several neurodegenerative disorders. Th e widespread nervous system expression of ciliary neurotrophic factor recep tor components and the effects of low ciliary neurotrophic factor concentra tions on a wide variety of cells in culture combine to suggest that functio nal ciliary neurotrophic factor receptors are expressed by many classes of neurons in vivo. However, the in vice 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 neuro trophic 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 dend rites. 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 ne urons 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 elic it the same cell-type-dependent pattern of phospho-STAT3 increases. Respons ive and non-responsive neurons express comparable levels of STAT3. Therefore, in vivo ciliary neurotrophic factor receptor-initiated STAT3 sig nal transduction is regulated in a very cell-type-dependent manner. The pre sent 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 similarl y regulated. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights r eserved.