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Genetic reduction of embryonic leukemia-inhibitory factor production rescues placentation in SOCS3-null embryos but
Lorraine Robb1, Kristy Boyle, Steven Rakar
1The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. robb@wehi.edu.au
Abstract:
The suppressor of cytokine-signaling (SOCS) proteins act as negative-feedback inhibitors of cytokine and growth-factor-induced signal transduction. In vivo studies have implicated SOCS3 as a negative regulator of signaling downstream of gp130, the receptor subunit shared by IL-6-like cytokines. Mice lacking SOCS3 die at midgestation because of placental failure, and SOCS3 ablation in a cell-type-specific manner results in changes in the functional outcome of gp130 signaling in response to IL-6. In this study, we show that genetic reduction of leukemia-inhibitory factor (LIF) production by embryo-derived tissues is sufficient to prevent the placental defect. This establishes LIF signaling as a major physiological regulator of trophoblast differentiation in vivo. Mice deficient in both SOCS3 and LIF are born in predicted numbers and appear normal at birth but exhibit failure to thrive and high neonatal mortality. Adult SOCS3-null mice on a LIF-null background succumb to a spontaneous fatal inflammatory disease characterized by neutrophilia and inflammatory-cell tissue infiltrates. The disease spectrum mimics that seen in mice with a conditional deletion of SOCS3 in hematopoietic and endothelial cells, extending the evidence for a major role for SOCS3 in the homeostatic regulation of the inflammatory response and indicates that LIF is not required for this process.
Insights
Suppressor of cytokine-signaling 3 (SOCS3) regulates inflammation and development. Genetic reduction of leukemia-inhibitory factor (LIF) prevents SOCS3-deficiency placental defects, but combined deficiencies cause neonatal mortality and inflammatory disease.
Area of Science:
- Immunology
- Developmental Biology
- Molecular Signaling
Background:
- Suppressor of cytokine-signaling (SOCS) proteins are negative-feedback regulators of cytokine and growth factor signaling.
- SOCS3 is a known negative regulator of gp130-mediated signaling, crucial for IL-6-like cytokines.
- SOCS3 deficiency in mice leads to midgestation embryonic lethality due to placental failure.
Purpose of the Study:
- To investigate the role of leukemia-inhibitory factor (LIF) in SOCS3-deficient placental defects.
- To determine the combined effects of SOCS3 and LIF deficiency on embryonic development and adult inflammatory responses.
Main Methods:
- Genetic manipulation of SOCS3 and LIF in mouse models.
- Analysis of embryonic development, placental morphology, and neonatal survival.
- Assessment of inflammatory disease phenotypes in adult SOCS3-null/LIF-null mice.
Main Results:
- Genetic reduction of LIF production prevents placental defects in SOCS3-deficient mice, highlighting LIF's role in trophoblast differentiation.
- Mice deficient in both SOCS3 and LIF exhibit normal birth numbers but suffer high neonatal mortality.
- Adult SOCS3-null mice on a LIF-null background develop fatal inflammatory disease, independent of LIF.
Conclusions:
- LIF signaling is a critical regulator of trophoblast differentiation in vivo.
- SOCS3 plays a vital role in preventing spontaneous inflammatory diseases, independent of LIF.
- Combined SOCS3 and LIF deficiency reveals complex interplay in development and inflammation homeostasis.
