Leukemia inhibitory factor inhibits neuronal terminal differentiation through STAT3 activation.
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.
Moon
Cheil
C
Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Yoo
Joo-Yeon
JY
Matarazzo
Valéry
V
Sung
Young Kwan
YK
Kim
Esther J
EJ
Ronnett
Gabriele V
GV
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*
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