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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.
Abstract:
Numerous studies have indicated that BMP4 signaling is involved in the regulation of the early steps of development. In mouse embryonic stem cells (ESCs), BMP4 is crucial to sustain pluripotency and blocks differentiation towards neural fate. Here, through a systematic analysis of miRNAs in ESCs, we establish that BMP4 signaling regulates miR-23a, 27a and 24-2, through the recruitment of phospho-Smads at the promoter of the gene encoding this miRNA cluster. Suppression of miR-23a/b, 27a/b and 24 does not affect self-renewal or pluripotency, but induces an evident change of ESC differentiation, with a significant increase of the cells undergoing apoptosis after the transition from ESCs to epiblast stem cells (EpiSCs). BMP4 has been previously reported to cause apoptosis during ESC differentiation. By blocking BMP4 signaling, we completely prevent the apoptosis induced by suppression of the miRs. This suggests that the effects of miR suppression are the result of enhanced BMP4 signaling. This hypothesis is further supported by the observation that Smad5, the transcription factor downstream of the BMP4 receptor, is targeted by the miRNAs of the 23a and 23b clusters. Altogether, our results highlight the existence of a regulatory loop, involving Smad5 and the miR-23a clusters, that modulates the apoptotic response of ESCs to BMP4.
Insights
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.
