title: Leukemia inhibitory factor inhibits neuronal terminal differentiation through STAT3 activation.
abstract: The discovery of stem cells in the adult central nervous system raises questions concerning the neurotrophic factors that regulate postnatal neuronal development. Olfactory receptor neurons (ORNs) are a useful model, because they are capable of robust neurogenesis throughout adulthood. We have investigated the role of leukemia inhibitory factor (LIF) in postnatal neuronal development by using ORNs as a model. LIF is a multifunctional cytokine implicated in various aspects of neuronal development, including phenotype determination, survival, and in response to nerve injury. LIF-deficient mice display significant increases, both in the absolute amount and in the number of cells expressing olfactory marker protein, a marker of mature ORNs. The maturation of ORNs was significantly inhibited by LIF in vitro. LIF activated the STAT3 pathway in ORNs, and transfection of ORNs with a dominant negative form of STAT3 abolished the effect of LIF. These findings demonstrate that LIF negatively regulates ORN maturation via the STAT3 pathway. Thus, LIF plays a critical role in controlling the transition of ORNs to maturity. Consequently, a population of ORNs is maintained in an immature state to facilitate the rapid repopulation of the olfactory epithelium with mature neurons during normal cell turnover or after injury.
authors.affiliation: Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Cheil
authors.initials: C
authors.lastname: Moon
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Yoo
authors.forename: Valéry
authors.initials: V
authors.lastname: Matarazzo
authors.forename: Young Kwan
authors.initials: YK
authors.lastname: Sung
authors.forename: Esther J
authors.initials: EJ
authors.lastname: Kim
authors.forename: Gabriele V
authors.initials: GV
authors.lastname: Ronnett
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D004247:DNA; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006131:Growth Inhibitors / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D051842:Olfactory Marker Protein; D018034:Olfactory Receptor Neurons / Q000166:cytology*; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D009419:Nerve Tissue Proteins; D051842:Olfactory Marker Protein; C497598:Omp protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D004247:DNA