Identification of Vascular and Hematopoietic Genes Downstream of etsrp by Deep Sequencing in Zebrafish

Gomez, Gustavo A.; Lee, Jae Hyung; Veldman, Matthew B.; Lü, Jing; Xiao, Xinshu; Lin, Shuo

doi:10.1371/journal.pone.0031658

Cited by 29 publications

(26 citation statements)

References 66 publications

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“…Whole-mount analyses at 19 and 24 hpf revealed that tmem88a is expressed within the primordial heart field but seems to be more expansively expressed in the emerging vasculature (Fig. 2D,E,I,J), consistent with the findings of Gomez et al (Gomez et al, 2012).…”

Section: Resultssupporting

confidence: 89%

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Transmembrane protein 88: a Wnt regulatory protein that specifies cardiomyocyte development

et al. 2013

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SUMMARYGenetic regulation of the cell fate transition from lateral plate mesoderm to the specification of cardiomyocytes requires suppression of Wnt/β-catenin signaling, but the mechanism for this is not well understood. By analyzing gene expression and chromatin dynamics during directed differentiation of human embryonic stem cells (hESCs), we identified a suppressor of Wnt/β-catenin signaling, transmembrane protein 88 (TMEM88), as a potential regulator of cardiovascular progenitor cell (CVP) specification. During the transition from mesoderm to the CVP, TMEM88 has a chromatin signature of genes that mediate cell fate decisions, and its expression is highly upregulated in advance of key cardiac transcription factors in vitro and in vivo. In early zebrafish embryos, tmem88a is expressed broadly in the lateral plate mesoderm, including the bilateral heart fields. Short hairpin RNA targeting of TMEM88 during hESC cardiac differentiation increases Wnt/β-catenin signaling, confirming its role as a suppressor of this pathway. TMEM88 knockdown has no effect on NKX2.5 or GATA4 expression, but 80% of genes most highly induced during CVP development have reduced expression, suggesting adoption of a new cell fate. In support of this, analysis of later stage cell differentiation showed that TMEM88 knockdown inhibits cardiomyocyte differentiation and promotes endothelial differentiation. Taken together, TMEM88 is crucial for heart development and acts downstream of GATA factors in the pre-cardiac mesoderm to specify lineage commitment of cardiomyocyte development through inhibition of Wnt/β-catenin signaling.

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Section: Resultssupporting

confidence: 89%

“…Interestingly, results from Gomez et al (Gomez et al, 2012) show that Tmem88 is expressed in the posterior mesoderm in the developing vasculature of the zebrafish. In situ hybridization data shown here also indicate that Tmem88 is expressed in the developing vasculature.…”

Section: Discussionmentioning

confidence: 99%

Transmembrane protein 88: a Wnt regulatory protein that specifies cardiomyocyte development

et al. 2013

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“…Furthermore, we noted concomitant reduction in fli1a, fli1b, hey2, lmo2, tal1, kdrl , and flt4 in let-7a duplex-injected embryos (Fig. 5B), consistent with the observation that ectopic Etv2 can induce expression of these endothelial genes in zebrafish embryos (Gomez et al, 2012; Gomez et al, 2009; Wong et al, 2009). Co-injection of etv2 mRNA containing a heterologous 3’UTR along with let-7a duplex rescued the expression of these Etv2-responsive genes, suggesting that they are not directly targeted by let-7a (Fig.…”

Section: Resultssupporting

confidence: 88%

“…The severe early vascular defects and global effects on endothelial gene expression in both mouse and zebrafish embryos suggests that etv2 plays an early role in specifying endothelial cell lineages. Consistent with this possibility, overexpression Etv2 in both zebrafish embryos and mouse embryoid bodies can expand endothelial cell lineages and induce concomitant expression of hundreds of vascular genes (Gomez et al, 2012; Koyano-Nakagawa et al, 2012; Sumanas and Lin, 2006; Wong et al, 2009). Furthermore, recent studies demonstrate that Etv2 is an essential component, along with Fli1 and Erg, during direct endothelial reprogramming of human amniotic cells (Ginsberg et al, 2012).…”

Section: Introductionmentioning

confidence: 72%

Post-transcriptional mechanisms contribute to Etv2 repression during vascular development

Moore¹,

Sheppard-Tindell²,

Shestopalov³

et al. 2013

Developmental Biology

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etv2 is an endothelial-specific ETS transcription factor that is essential for vascular differentiation and morphogenesis in vertebrates. While recent data suggest that Etv2 is dynamically regulated during vascular development, little is known about the mechanisms involved in this process. Here, we find that etv2 transcript and protein expression are highly dynamic during zebrafish vascular development, with both apparent during early somitogenesis and subsequently down-regulated as development proceeds. Inducible knockdown of Etv2 in zebrafish embryos prior to mid-somitogenesis stages, but not later, caused severe vascular defects, suggesting a specific role in early commitment of lateral mesoderm to the endothelial linage. Accordingly, Etv2-overexpressing cells showed an enhanced ability to commit to endothelial lineages in mosaic embryos. We further find that the etv2 3’ untranslated region (UTR) is capable of repressing an endothelial autonomous transgene and contains binding sites for members of the let-7 family of microRNAs. Ectopic expression of let-7a could repress the etv2 3’UTR in sensor assays and was also able to block endogenous Etv2 protein expression, leading to concomitant reduction of endothelial genes. Finally, we observed that Etv2 protein levels persisted in maternal-zygotic dicer1 mutant embryos, suggesting that microRNAs contribute to its repression during vascular development. Taken together, our results suggest that etv2 acts during early development to specify endothelial lineages and is then down-regulated, in part through post-transcriptional repression by microRNAs, to allow normal vascular development.

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“…However, despite the abundance and importance of these regulators in the spatio-temporal control of Rac1 function, little is known about their implication during vascular development24. In particular, CdGAP (Cdc42 GTPase-activating protein)/ARHGAP31, a GAP for Rac1 and Cdc422526, was reported to be highly expressed in human umbilical vein endothelial cells (HUVECs)24, and to be regulated in Zebrafish by the transcription factor Ets, a master regulator of angiogenesis2728. Outside of the vascular system, pro-migratory and pro-invasive functions were ascribed to CdGAP, which was shown to regulate directional membrane protrusions of migrating osteosarcoma cells293031 and TGFβ-dependent cell motility and invasion of breast cancer cells32.…”

mentioning

confidence: 99%

CdGAP/ARHGAP31, a Cdc42/Rac1 GTPase regulator, is critical for vascular development and VEGF-mediated angiogenesis

Caron

DeGeer

Fournier

et al. 2016

Sci Rep

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Mutations in the CdGAP/ARHGAP31 gene, which encodes a GTPase-activating protein for Rac1 and Cdc42, have been reported causative in the Adams-Oliver developmental syndrome often associated with vascular defects. However, despite its abundant expression in endothelial cells, CdGAP function in the vasculature remains unknown. Here, we show that vascular development is impaired in CdGAP-deficient mouse embryos at E15.5. This is associated with superficial vessel defects and subcutaneous edema, resulting in 44% embryonic/perinatal lethality. VEGF-driven angiogenesis is defective in CdGAP−/− mice, showing reduced capillary sprouting from aortic ring explants. Similarly, VEGF-dependent endothelial cell migration and capillary formation are inhibited upon CdGAP knockdown. Mechanistically, CdGAP associates with VEGF receptor-2 and controls VEGF-dependent signaling. Consequently, CdGAP depletion results in impaired VEGF-mediated Rac1 activation and reduced phosphorylation of critical intracellular mediators including Gab1, Akt, PLCγ and SHP2. These findings are the first to demonstrate the importance of CdGAP in embryonic vascular development and VEGF-induced signaling, and highlight CdGAP as a potential therapeutic target to treat pathological angiogenesis and vascular dysfunction.

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Identification of Vascular and Hematopoietic Genes Downstream of etsrp by Deep Sequencing in Zebrafish

Cited by 29 publications

References 66 publications

Transmembrane protein 88: a Wnt regulatory protein that specifies cardiomyocyte development

Transmembrane protein 88: a Wnt regulatory protein that specifies cardiomyocyte development

Post-transcriptional mechanisms contribute to Etv2 repression during vascular development

CdGAP/ARHGAP31, a Cdc42/Rac1 GTPase regulator, is critical for vascular development and VEGF-mediated angiogenesis

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