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14-3-3ζ loss leads to neonatal lethality by microRNA-126 downregulation-mediated developmental defects in lung
Jun Yang1,2, Sonali Joshi1, Qingfei Wang1
1Department of Molecular and Cellular Oncology, Unit 108, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 USA.
Background:
The 14-3-3 family of proteins have been reported to play an important role in development in various mouse models, but the context specific developmental functions of 14-3-3ζ remain to be determined. In this study, we identified a context specific developmental function of 14-3-3ζ.
Results:
Targeted deletion of 14-3-3ζ in the C57Bl/6J murine genetic background led to neonatal lethality due to respiratory distress and could be rescued by out-breeding to the CD-1 or backcrossing to the FVB/NJ congenic background. Histological analysis of lung sections from 18.5 days post coitum embryos (dpc) showed that 14-3-3ζ-/- lung development is arrested at the pseudoglandular stage and exhibits vascular defects. The expression of miR-126, an endothelial-specific miRNA known to regulate lung vascular integrity was down-regulated in the lungs of the 14-3-3ζ-/- embryos in the C57Bl/6J background as compared to their wild-type counterparts. Loss of 14-3-3ζ in endothelial cells inhibited the angiogenic capability of the endothelial cells as determined by both trans-well migration assays and tube formation assays and these defects could be rescued by re-expressing miR-126. Mechanistically, loss of 14-3-3ζ led to reduced Erk1/2 phosphorylation resulting in attenuated binding of the transcription factor Ets2 on the miR-126 promoter which ultimately reduced expression of miR-126.
Conclusion:
Our data demonstrates that miR-126 is an important angiogenesis regulator that functions downstream of 14-3-3ζ and downregulation of miR-126 plays a critical role in 14-3-3ζ-loss induced defects in lung vasculature in the C57Bl/6J genetic background.
Insights
Loss of 14-3-3ζ protein in mice causes respiratory distress and lung vascular defects. This is linked to reduced miR-126, an important regulator of blood vessel formation.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- The 14-3-3 protein family plays vital roles in development, but the specific functions of 14-3-3ζ are not fully understood.
- This study investigates the context-specific developmental role of 14-3-3ζ.
Purpose of the Study:
- To determine the specific developmental function of 14-3-3ζ.
- To elucidate the molecular mechanisms underlying 14-3-3ζ-dependent lung development.
Main Methods:
- Targeted deletion of 14-3-3ζ in C57Bl/6J mice.
- Histological analysis of embryonic lung development.
- Assessment of endothelial cell function (migration, tube formation).
- Analysis of miR-126 expression and its regulatory pathway (Erk1/2, Ets2).
Main Results:
- 14-3-3ζ deletion caused neonatal lethality with respiratory distress and lung vascular defects, arrest at the pseudoglandular stage.
- miR-126 expression was downregulated in 14-3-3ζ-deficient lungs, impairing endothelial cell angiogenesis.
- Loss of 14-3-3ζ reduced Erk1/2 phosphorylation, affecting Ets2 binding to the miR-126 promoter.
Conclusions:
- miR-126 is a critical downstream target of 14-3-3ζ in regulating lung vascular integrity.
- Downregulation of miR-126 is a key factor in 14-3-3ζ deficiency-induced lung defects in the C57Bl/6J background.
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