miR-142-3p Controls the Specification of Definitive Hemangioblasts during Ontogeny

Nimmo, Rachael; Ciau-Uitz, Aldo; Ruiz-Herguido, Cristina; Soneji, Shamit; Bigas, Anna; Patient, Roger; Enver, Tariq

doi:10.1016/j.devcel.2013.06.023

Cited by 63 publications

(70 citation statements)

References 61 publications

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“…Based on our present findings, we speculate that a similar phenotype would be observed at the onset of definitive hematopoiesis in miR-142 −/− KO mice. Interestingly, a very recent report showed that in Xenopus, miR-142-3p is required for HSC lineage specification [37], which is consistent with the results for zebrafish and mouse embryos reported in this study. In contrast, an inverse correlation between miR-142-3p expression and HSC development has been suggested recently [20].…”

Section: Discussionsupporting

confidence: 93%

miR-142-3p regulates the formation and differentiation of hematopoietic stem cells in vertebrates

et al. 2013

Cell Res

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Previous studies on developmental hematopoiesis have mainly focused on signaling and transcription factors, while the appreciation of epigenetic regulation including that of microRNAs is recent. Here, we show that in zebrafish and mouse, miR-142-3p is specifically expressed in hematopoietic stem cells (HSCs). Knockdown of miR-142a-3p in zebrafish led to a reduced population of HSCs in the aorta-gonad-mesonephros (AGM) region as well as T-cell defects in the thymus. Mechanistically, miR-142a-3p regulates HSC formation and differentiation through the repression of interferon regulatory factor 7 (irf7)-mediated inflammation signaling. Finally, we show that miR-142-3p is also involved in the development of HSCs in mouse AGM, suggesting that it has a highly conserved role in vertebrates. Together, these findings unveil the pivotal roles that miR-142a-3p plays in the formation and differentiation of HSCs by repressing irf7 signaling.

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Section: Discussionsupporting

confidence: 93%

miR-142-3p regulates the formation and differentiation of hematopoietic stem cells in vertebrates

et al. 2013

Cell Res

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“…Consistent with the ratio of the miR-K10a 5 ′ -isomiRs detected by deep sequencing (Supplemental Table S2; Gottwein et al 2011), the miRK10a 5 ′ -isomiR is slightly more abundant in PEL cell lines than miR-K10a+1. Because of the emerging pivotal role of miR-142-3p in the vertebrate hematopoietic lineage (Nishiyama et al 2012;Mildner et al 2013;Nimmo et al 2013;Chapnik et al 2014), we assessed whether the expression of mature miR-142-3p−1 is conserved beyond mice and humans. The predicted mature miR-142-3p/−1 sequences are invariant across vertebrates (http://genome.ucsc .edu/), but less conserved portions of the pri-miRNA could lead to differences in isomiR expression.…”

Section: Mir-142-3p 5 ′ -Isomir Expression Is Conserved In Vertebratesmentioning

confidence: 99%

“…Overexpression of the miR-142 precursor in mouse hematopoietic progenitor cells substantially increases the T-cell population in vitro (Chen et al 2004). The inactivation of miR-142-3p causes defects in hematopoiesis in zebrafish (Nishiyama et al 2012) and prevents the specification of definitive hemangioblasts in Xenopus (Nimmo et al 2013). In mice, ablation of the miR-142 locus results in reduced numbers of CD4 + dendritic cells (Mildner et al 2013) and a severe impairment of platelet formation (Chapnik et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Divergent target recognition by coexpressed 5′-isomiRs of miR-142-3p and selective viral mimicry

Manzano

Forte

Raja

et al. 2015

RNA

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Sequence heterogeneity at the ends of mature microRNAs (miRNAs) is well documented, but its effects on miRNA function are largely unexplored. Here we studied the impact of miRNA 5 ′ -heterogeneity, which affects the seed region critical for target recognition. Using the example of miR-142-3p, an emerging regulator of the hematopoietic lineage in vertebrates, we show that naturally coexpressed 5 ′ -variants (5 ′ -isomiRs) can recognize largely distinct sets of binding sites. Despite this, both miR-142-3p isomiRs regulate exclusive and shared targets involved in actin dynamics. Thus, 5′ -heterogeneity can substantially broaden and enhance regulation of one pathway. Other 5 ′ -isomiRs, in contrast, recognize largely overlapping sets of binding sites. This is exemplified by two herpesviral 5 ′ -isomiRs that selectively mimic one of the miR-142-3p 5 ′ -isomiRs. We hypothesize that other cellular and viral 5 ′ -isomiRs can similarly be grouped into those with divergent or convergent target repertoires, based on 5 ′ -sequence features. Taken together, our results provide a detailed characterization of target recognition by miR-142-3p and its 5 ′ -isomiR-specific viral mimic. We furthermore demonstrate that miRNA 5 ′ -end variation leads to differential targeting and can thus broaden the target range of miRNAs.

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“…Hence, we aim to understand the signaling events in the setting up of the transcription factor networks necessary for HSC generation. To this end, we have characterized the GRN architecture before HE specification extensively, and identified positive inputs from vegfa splice isoforms into this network as well as an inhibitory effect by TGFB signaling at early stages of hemangioblast formation (9,14,44). The current analysis furthers our understanding by dissecting the role of BMP signaling with regard to the definitive blood transcription network.…”

Section: Discussionmentioning

confidence: 74%

“…(9). Meanwhile, TGFB signaling has an inhibitory effect on fli1 expression (44). BMP signaling, presumably through activation Smad transcription factors, together with Fli1, is first required for gata2 expression before stage 20 (*1) and then for kdr expression at stage 20 (*2) (current study).…”

Section: Acknowledgments This Work Was Supported By the Uk Medical Rmentioning

confidence: 67%

Dissecting BMP signaling input into the gene regulatory networks driving specification of the blood stem cell lineage

Kirmizitas

Meiklejohn

Ciau-Uitz

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Hematopoietic stem cells (HSCs) that sustain lifelong blood production are created during embryogenesis. They emerge from a specialized endothelial population, termed hemogenic endothelium (HE), located in the ventral wall of the dorsal aorta (DA). In Xenopus, we have been studying the gene regulatory networks (GRNs) required for the formation of HSCs, and critically found that the hemogenic potential is defined at an earlier time point when precursors to the DA express hematopoietic as well as endothelial genes, in the definitive hemangioblasts (DHs). The GRN for DH programming has been constructed and, here, we show that bone morphogenetic protein (BMP) signaling is essential for the initiation of this GRN. BMP2, -4, and -7 are the principal ligands expressed in the lineage forming the HE. To investigate the requirement and timing of all BMP signaling in HSC ontogeny, we have used a transgenic line, which inducibly expresses an inhibitor of BMP signaling, Noggin, as well as a chemical inhibitor of BMP receptors, DMH1, and described the inputs from BMP signaling into the DH GRN and the HE, as well as into primitive hematopoiesis. BMP signaling is required in at least three points in DH programming: first to initiate the DH GRN through gata2 expression, then for kdr expression to enable the DH to respond to vascular endothelial growth factor A (VEGFA) ligand from the somites, and finally for gata2 expression in the DA, but is dispensable for HE specification after hemangioblasts have been formed.

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miR-142-3p Controls the Specification of Definitive Hemangioblasts during Ontogeny

Cited by 63 publications

References 61 publications

miR-142-3p regulates the formation and differentiation of hematopoietic stem cells in vertebrates

miR-142-3p regulates the formation and differentiation of hematopoietic stem cells in vertebrates

Divergent target recognition by coexpressed 5′-isomiRs of miR-142-3p and selective viral mimicry

Dissecting BMP signaling input into the gene regulatory networks driving specification of the blood stem cell lineage

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