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miR-23a, miR-24 and miR-27a protect differentiating ESCs from BMP4-induced apoptosis
A Musto1, A Navarra1, A Vocca1
11] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Via Sergio Pansini 5, Naples, Italy [2] Ceinge Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.
Cell Death and Differentiation
|December 6, 2014
Summary
Bone morphogenetic protein 4 (BMP4) signaling regulates miR-23a clusters in mouse embryonic stem cells (ESCs). This interaction modulates apoptosis during differentiation, revealing a novel regulatory loop involving Smad5.
Area of Science:
- Developmental Biology
- Stem Cell Biology
- Molecular Biology
Background:
- Bone morphogenetic protein 4 (BMP4) signaling is vital for early development, maintaining pluripotency and inhibiting neural differentiation in mouse embryonic stem cells (ESCs).
- MicroRNAs (miRNAs) are key regulators of gene expression, influencing various cellular processes including differentiation and apoptosis.
Purpose of the Study:
- To investigate the role of BMP4 signaling in regulating specific miRNAs during ESC differentiation.
- To elucidate the functional consequences of miRNA regulation by BMP4 on ESC fate and apoptosis.
Main Methods:
- Systematic analysis of miRNAs in ESCs.
- Investigating the recruitment of phospho-Smads to miRNA gene promoters.
- Assessing the effects of miRNA suppression on ESC self-renewal, pluripotency, differentiation, and apoptosis.
- Modulating BMP4 signaling to determine its impact on miRNA suppression-induced apoptosis.
- Analyzing the targeting of Smad5 by specific miRNAs.
Main Results:
- BMP4 signaling directly regulates the miR-23a, miR-27a, and miR-24-2 cluster through phospho-Smad recruitment.
- Suppression of these miRNAs does not affect ESC self-renewal or pluripotency but enhances apoptosis during the ESC to epiblast stem cell (EpiSC) transition.
- Blocking BMP4 signaling abrogates the apoptosis induced by miRNA suppression, indicating BMP4 signaling mediates this effect.
- Smad5, a downstream transcription factor of BMP4, is a target of the miR-23a/b clusters.
Conclusions:
- A regulatory loop exists between Smad5 and the miR-23a clusters that controls the apoptotic response of ESCs to BMP4 signaling.
- This loop plays a critical role in modulating ESC differentiation and survival during early developmental transitions.
