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Updated: Aug 15, 2026
Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development
Published on: June 15, 2017
LIGHT induces differentiation of mouse embryonic stem cells associated with activation of ERK5
1Department of Internal Medicine, University of Iowa School of Medicine, Iowa City, IA, USA. gzou@iupui.edu
Abstract:
LT-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells (LIGHT) is a recently cloned type II transmembrane protein belonging to the TNF family that was originally identified as a weak inducer of apoptosis. This cytokine has been extensively defined in its role on T-cell regulation and dendritic cell maturation. However, whether this cytokine regulates stem cell proliferation and/or differentiation remains unknown. In this study, we transduced exogenous LIGHT into embryonic stem cells (ES cells) and found it induced their differentiation. The expression of phospho-STAT3, Nanog and Oct-4 was reduced in LIGHT-transduced ES cells compared with wild-type ES cells. LIGHT-transduced ES cells exhibit a low level of SSEA-1 surface antigen and alkaline phosphatase staining compared with wild-type cells. Introduction of LIGHT into ES cells results in the dephosphorylation of MKP-3 and activation of extracellular signal-regulated kinase (ERK)5. When ERK5 was inhibited by the specific inhibitor PD184352 or knocked down by ERK5 siRNA, reduction of Oct-4 and SSEA-1 expression was rescued. We conclude that LIGHT overrides Leukemia inhibitory factor to induce ES cell differentiation associated with activation of ERK5.
Insights
Tumor necrosis factor superfamily member LIGHT induces embryonic stem cell differentiation by activating extracellular signal-regulated kinase 5 (ERK5). This process overrides the effects of Leukemia inhibitory factor, impacting key stem cell markers.
Area of Science:
- Stem cell biology
- Immunology
- Molecular biology
Background:
- Tumor necrosis factor superfamily member LIGHT is known for its roles in T-cell regulation and dendritic cell maturation.
- Its function in regulating embryonic stem cell (ES cell) proliferation and differentiation has not been previously established.
Purpose of the Study:
- To investigate the role of LIGHT in the regulation of embryonic stem cell differentiation.
- To elucidate the molecular mechanisms underlying LIGHT-induced stem cell differentiation.
Main Methods:
- Transduction of exogenous LIGHT into mouse embryonic stem cells (ES cells).
- Analysis of stem cell marker expression (Nanog, Oct-4, SSEA-1, alkaline phosphatase).
- Assessment of signaling pathway activation (phospho-STAT3, MKP-3, extracellular signal-regulated kinase 5 [ERK5]).
- Pharmacological inhibition and siRNA knockdown of ERK5.
Main Results:
- LIGHT transduction induced ES cell differentiation, characterized by reduced expression of pluripotency markers (Nanog, Oct-4) and surface antigens (SSEA-1).
- LIGHT treatment led to decreased phospho-STAT3 and dephosphorylation of MKP-3, subsequently activating ERK5.
- Inhibition or knockdown of ERK5 rescued the expression of Oct-4 and SSEA-1, indicating its critical role in LIGHT-induced differentiation.
Conclusions:
- LIGHT overrides Leukemia inhibitory factor (LIF) signaling to induce ES cell differentiation.
- The differentiation process is mediated through the activation of the ERK5 signaling pathway.
- LIGHT represents a novel factor influencing stem cell fate decisions.
