Hedgehog signaling via angiopoietin1 is required for developmental vascular stability

Lamont, Ryan E.; Vu, Wendy; Carter, Alyson D.; Serluca, Fabrizio C.; MacRae, Calum A.; Childs, Sarah J.

doi:10.1016/j.mod.2010.02.001

Cited by 38 publications

(59 citation statements)

References 41 publications

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“…Besides the typical ciliary phenotypes reported in the previous study , we further found that the mRNA splicing inhibited-zebrafish had disrupted vasculature systems (Figure 4(c)). These malformed blood vessels are also known ciliary defects (Lamont et al 2010;Goetz et al 2014), and thus our data suggest that mRNA splicing is involved in a ciliogenesis control.…”

Section: Inhibition Of Mrna Splicing Causes Ciliary Defectssupporting

confidence: 61%

Mitotic control by mRNA splicing regulators ensures primary cilia formation

Kim

Lee

2016

Animal Cells and Systems

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The biogenesis of the primary cilium is coordinated with cell cycle exit/re-entry in most types of cells. After serum starvation, the cilia-generating cells enter quiescence and produce the primary cilium; upon re-addition of serum, they re-enter the cell cycle and resorb the cilium. We previously identified novel mechanisms to link cell cycle progression and ciliogenesis by highcontent genome-wide RNAi cell-based screening. In the present study, we pay attention to reveal the impact of mRNA splicing on cilia assembly after mitosis of cell cycle. We demonstrate that splicing regulators such as SON and XAB2 play an important role in mitosis exit, and thus affect ciliogenesis in G1/G0 phases. Knockdown of the splicing regulators in hTERT-RPE1 cells caused abnormal G2/M arrest under both serum addition and serum starvation, indicating defects in mitosis exit. Moreover, the knockdown cells failed to assemble the cilia under serum starvation and an inhibition of mRNA splicing using SSA, a spliceosome inhibitor, also revealed ciliogenesis defect. Finally, we show that the SSA-treated zebrafish display abnormal vascular development as a ciliary defect. These findings suggest the pivotal role of mRNA splicing regulators in cilia assembly and underscore the importance of mitotic regulation in ciliogenesis.ARTICLE HISTORY

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Section: Inhibition Of Mrna Splicing Causes Ciliary Defectssupporting

confidence: 61%

Mitotic control by mRNA splicing regulators ensures primary cilia formation

Kim

Lee

2016

Animal Cells and Systems

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“…Mural cells of the AMA and DA express early VSMC markers (62,65,77) and the pericyte marker PDGF receptor b (pdgfrb) in the DA (74). However, these cells lack myofilaments and cytoskeletal plaques, which is consistent with undifferentiated and noncontractile cells (39,48,62). Due to low circulatory pressures in fish (62,77), AMA mural cells may not directly impact on vascular tone but rather perform angiogenic and endocrine functions.…”

Section: Discussionmentioning

confidence: 99%

Renin expression in developing zebrafish is associated with angiogenesis and requires the Notch pathway and endothelium

Rider

Mullins

Verdon

et al. 2015

American Journal of Physiology-Renal Physiology

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Rider SA, Mullins LJ, Verdon RF, MacRae CA, Mullins JJ. Renin expression in developing zebrafish is associated with angiogenesis and requires the Notch pathway and endothelium. Am J Physiol Renal Physiol 309: F531-F539, 2015. First published July 22, 2015 doi:10.1152/ajprenal.00247.2015.-Although renin is a critical regulatory enzyme of the cardiovascular system, its roles in organogenesis and the establishment of cardiovascular homeostasis remain unclear. Mammalian renin-expressing cells are widespread in embryonic kidneys but are highly restricted, specialized endocrine cells in adults. With a functional pronephros, embryonic zebrafish are ideal for delineating the developmental functions of renin-expressing cells and the mechanisms governing renin transcription. Larval zebrafish renin expression originates in the mural cells of the juxtaglomerular anterior mesenteric artery and subsequently at extrarenal sites. The role of renin was determined by assessing responses to renin-angiotensin system blockade, salinity variation, and renal perfusion ablation. Renin expression did not respond to renal flow ablation but was modulated by inhibition of angiotensin-converting enzyme and altered salinity. Our data in larval fish are consistent with conservation of renin's physiological functions. Using transgenic renin reporter fish, with mindbomb and cloche mutants, we show that Notch signaling and the endothelium are essential for developmental renin expression. After inhibition of angiogenesis, renin-expressing cells precede angiogenic sprouts. Arising from separate lineages, but relying on mutual interplay with endothelial cells, renin-expressing cells are among the earliest mural cells observed in larval fish, performing both endocrine and paracrine functions. renin; zebrafish; notch; endothelium; angiogenesis RENIN is the rate-limiting enzyme of the renin-angiotensin system (RAS). Mammalian ANG II, the effector of the RAS, is principally involved in blood pressure homeostasis by regulation of vasomotor tone and Na ϩ retention. ANG II also regulates cell proliferation and angiogenesis (12,22). Pathological activation of the RAS is associated with cardiovascular diseases, including hypertension and heart failure, and is consequently a major target of therapeutic agents (11).Renin and its cognate cells are required for normal renal development (2), including angiogenesis of the renal vascular tree (59). In mice, ablation of the renin gene or renin-expressing cells leads to renal developmental abnormalities (55,71,79). The vasculature of mammalian embryonic kidneys have a transient but extensive coverage of mural renin-expressing cells (17,31,32,47,63); however, their function is unclear. Adult renin-expressing cells are restricted to the juxtaglomerular apparatus and play a vital role in ion homeostasis by secreting activated renin enzyme via cytoplasmic granules (17,31,36,63). Upon physiological challenge by RAS inhibition or low Na ϩ , prearteriolar vascular smooth muscle cells (VSMC) reestablish their embryonic re...

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“…27 Interestingly, previous work showed that treatment with cyclopamine, an antagonist of the Hedgehog pathway, causes ICH in zebrafish embryos reminiscent of the phenotype that we observed in IFT mutants, suggesting that this pathway may be important for developmental vascular integrity. 28 To investigate whether the Hedgehog pathway is associated with cilia-associated ICH, we first identified a suboptimal regimen of cyclopamine treatment by titrating the dosage and time window. Treatment with 25-30 mmol/L cyclopamine from 25 hpf did not change the embryo morphology significantly (Figure 4, A and B), which allowed us to identify mutant embryos unequivocally on the basis of their body curvature phenotype.…”

Section: Defective Hedgehog Signaling Is a Major Cause Of Ich In Ift mentioning

confidence: 99%

Endothelial Cilia Are Essential for Developmental Vascular Integrity in Zebrafish

Kallakuri¹,

Li³

et al. 2015

Journal of the American Society of Nephrology

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The cilium is a signaling platform of the vertebrate cell. It has a critical role in polycystic kidney disease and nephronophthisis. Cilia have been detected on endothelial cells, but the function of these organelles in the vasculature remains incompletely defined. In this study, using genetic and chemical genetic tools in the model organism zebrafish, we reveal an essential role of cilia in developmental vascular integrity. Embryos expressing mutant intraflagellar transport genes, which are essential and specific for cilia biogenesis, displayed increased risk of developmental intracranial hemorrhage, whereas the morphology of the vasculature remained normal. Moreover, cilia were present on endothelial cells in the developing zebrafish vasculature. We further show that the involvement of cilia in vascular integrity is endothelial autonomous, because endothelial-specific re-expression of intraflagellar transport genes in respective mutants rescued the intracranial hemorrhage phenotype. Finally, whereas inhibition of Hedgehog signaling increased the risk of intracranial hemorrhage in ciliary mutants, activation of the pathway rescued this phenotype. In contrast, embryos expressing an inactivating mutation in pkd2, one of two autosomal dominant cystic kidney disease genes, did not show increased risk of developmental intracranial hemorrhage. These results suggest that Hedgehog signaling is a major mechanism for this novel role of endothelial cilia in establishing vascular integrity.

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Hedgehog signaling via angiopoietin1 is required for developmental vascular stability

Cited by 38 publications

References 41 publications

Mitotic control by mRNA splicing regulators ensures primary cilia formation

Mitotic control by mRNA splicing regulators ensures primary cilia formation

Renin expression in developing zebrafish is associated with angiogenesis and requires the Notch pathway and endothelium

Endothelial Cilia Are Essential for Developmental Vascular Integrity in Zebrafish

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