Leukemia inhibitory factor inhibits neuronal terminal differentiation through STAT3 activation

Moon, Cheil; Yoo, Joo Yeon; Matarazzo, Valéry; Sung, Young Kwan; Kim, Esther J.; Ronnett, Gabriele V.

doi:10.1073/pnas.132131699

Cited by 80 publications

(67 citation statements)

References 62 publications

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“…Moon et al (2002) also showed that LIF inhibits the differentiation and maturation of immature olfactory receptor neurons via the activation of Stat3. In their study, a dominant negative form of Stat3 induced the premature differentiation of olfactory receptor neurons, indicating that Stat3 function is essential (Moon et al, 2002). Suzuki et al (2005) injected LIF into the boundary area of an ischemic infarct which rapidly induced Stat3 phosphorylation and a decreased the severity of insult.…”

Section: Discussionmentioning

confidence: 95%

“…Targeted mutagenesis in ES cell lines showed that inhibiting Stat3 rapidly induces differentiation (Raz et al, 1999). Moon et al (2002) also showed that LIF inhibits the differentiation and maturation of immature olfactory receptor neurons via the activation of Stat3. In their study, a dominant negative form of Stat3 induced the premature differentiation of olfactory receptor neurons, indicating that Stat3 function is essential (Moon et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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Leukemia inhibitory factor participates in the expansion of neural stem/progenitors after perinatal hypoxia/ischemia

Covey

Levison

2007

Neuroscience

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Subsequent to perinatal hypoxia/ischemia there is an increase in the number of neural stem/progenitor cells (NSP) within the subventricular zone. Gene expression analyses have implicated Notch signaling in the expansion of these tripotential cells but there are limited data as to which signals are stimulating Notch activation. There is evidence that the LIFR/gp130 receptor heterodimer induces Notch1 to maintain NSP populations during normal development. LIF and CNTF bind to these receptor components and they coordinate injury responses in the CNS. Therefore, the aim of these studies was to investigate whether CNTF and/or LIF participate in NSP expansion in the SVZ after H/I as well as to characterize the downstream events that regulate NSP numbers. We report that LIF mRNA is induced 48 hours post insult by 13 fold but that it returns almost to baseline by 72 hours. Commensurate with increased LIF expression there is a corresponding increase in phosphorylated STAT-3 within the SVZ. Modeling the changes that occur in vivo, we show that LIF induces STAT-3 phosphorylation in neurospheres to enhance Delta-like-1 and Notch1 expression as well as to increase Notch1 activation. LIF also expands neurosphere number and size in vitro. Whereas CNTF can mimic the effects of LIF in vitro, CNTF expression in the SVZ was unchanged during recovery from H/I. Cumulatively, these data implicate LIF and not CNTF in the expansion of NSPs in the SVZ after perinatal brain injury. As both LIF expression and the endogenous regenerative response after brain injury are time-delimited, these findings provide insights into strategies to expand the endogenous pool of NSPs to repopulate the damaged brain.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Leukemia inhibitory factor participates in the expansion of neural stem/progenitors after perinatal hypoxia/ischemia

Covey

Levison

2007

Neuroscience

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“…Consistently, STAT3 is strongly suggested by in vitro studies to play an instructive role in glial and neuron differentiation (11)(12)(13)(14). In adults, STAT3 has long been implicated in the regulation of energy homeostasis through the fat-derived cytokine leptin.…”

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confidence: 81%

Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation

Gao

Wolfgang

Neschen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

354

239

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Signal transducer and activator of transcription (STAT)3 is widely expressed in the CNS during development and adulthood. STAT3 has been implicated in the control of neuron͞glial differentiation and leptin-mediated energy homeostasis, but the physiological role and degree of involvement of STAT3 in these processes is not defined and controversial because of the lack of a direct genetic model. To address this, we created mice with a neural-specific disruption of STAT3 (STAT3 N؊/؊ ). Surprisingly, homozygous mutants were born at the expected Mendelian ratio without apparent developmental abnormalities but susceptible to neonatal lethality. Mutants that survived the neonatal period were hyperphagic, obese, diabetic, and infertile. Administering a melanocortin-3͞4 receptor agonist abrogated the hyperphagia and hypothalamic immunohistochemistry showed a marked reduction in proopiomelanocortin with an increase in neuropeptide Y and agouti-related protein. Mutants had reduced energy expenditure and became hypothermic after fasting or cold stress. STAT3 N؊/؊ mice are hyperleptinemic, suggesting a leptin-resistant condition. Concomitant with neuroendocrine defects such as decreased linear growth and infertility with accompanying increased corticosterone levels, this CNS knockout recapitulates the unique phenotype of db͞db and ob͞ob obese models and distinguishes them from other genetic models of obesity. Thus, STAT3 in the CNS plays essential roles in the regulation of energy homeostasis and reproduction. Signal transducer and activator of transcription (STAT) proteins are a group of cytokine-activated signaling molecules that can directly bind to DNA and activate or repress transcription of target genes. A myriad of cytokines activate STAT proteins through receptor-associated kinases. Activation of STATs occurs through tyrosine phosphorylation that is required for SH2 domain-mediated dimerization and DNA binding. Most STAT proteins have specific effects, but STAT3, the most ancient STAT, is broadly expressed and activated by a diverse array of cytokines and stresses (1-3). It was initially described as an acute phase protein involved in various biological and pathological processes. STAT3 deletion causes embryonic lethality before gastrulation via an unknown mechanism (4). STAT3 has unusually pleiotropic effects regulating murine embryonic stem cell maintenance (5), macrophage function (6, 7), immune regulation (8), and peripheral neuron survival after axotomy (9, 10) among others.In the CNS, STAT3 is expressed during embryonic development, mostly at ventricular areas, where neuronal proliferation and differentiation take place. Consistently, STAT3 is strongly suggested by in vitro studies to play an instructive role in glial and neuron differentiation (11)(12)(13)(14). In adults, STAT3 has long been implicated in the regulation of energy homeostasis through the fat-derived cytokine leptin. Although leptin can activate several STAT proteins, including STAT3, 5, and 6, in vitro (15), only STAT3 is activated in the hypoth...

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“…Among others, Stat3 plays critical roles in the early mouse development as shown by early embryonic lethality in Stat3-null mice (Takeda et al, 1997). In addition, involvement of Stat3 in glial and neuron differentiation also was suggested (Bonni et al, 1997;Takizawa et al, 2001;Moon et al, 2002). In adult mice, Stat3 is essential for motor neuron survival after lesion (Schweizer et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

The LIM/Homeodomain Protein Islet1 Recruits Janus Tyrosine Kinases and Signal Transducer and Activator of Transcription 3 and Stimulates Their Activities

Hao

Novotny‐Diermayr

Bian

et al. 2005

MBoC

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Islet1 (Isl1) belongs to the LIM homeodomain transcription factor family. Its roles in differentiation of motor neurons and organogenesis of pancreas and heart have been revealed. However, less is known about its regulatory mechanism and the target genes. In this study, we identified interactions between Isl1 and Janus tyrosine kinase (JAK), as well as signal transducer and activator of transcription (Stat)3, but not Stat1 and Stat5, in mammalian cells. We found that Isl1 not only forms a complex with Jak1 and Stat3 but also triggers the tyrosine phosphorylation of Jak1 and its kinase activity, thereby elevating the tyrosine phosphorylation, DNA binding activity, and target gene expression of Stat3. In vivo, the tyrosine-

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Leukemia inhibitory factor inhibits neuronal terminal differentiation through STAT3 activation

Cited by 80 publications

References 62 publications

Leukemia inhibitory factor participates in the expansion of neural stem/progenitors after perinatal hypoxia/ischemia

Leukemia inhibitory factor participates in the expansion of neural stem/progenitors after perinatal hypoxia/ischemia

Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation

The LIM/Homeodomain Protein Islet1 Recruits Janus Tyrosine Kinases and Signal Transducer and Activator of Transcription 3 and Stimulates Their Activities

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