Mutation of rnf213a by TALEN causes abnormal angiogenesis and circulation defects in zebrafish

Wen, Jun; Sun, Xunsha; Chen, Huimin; Liu, Huijiao; Lai, Rong; Li, Jiaoxing; Zhang, Jingjing; Sheng, Wenli

doi:10.1016/j.brainres.2016.04.051

Cited by 22 publications

(16 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PROK2 48 is an important contributor to tumor angiogenesis. Relevant to neonatal disease, LRG1 49 may contribute to the aberrant retinal vasculature observed in oxygen-induced retinopathy 49 , while RNF213 50 is required for normal vascular development. Of these, LRG1 is the only overlapping reported finding in the literature where FOSL1 knockdown in HUVECs decreased LRG1 to the same degree that we found in our immortalized HPMEC line.…”

Section: Discussionmentioning

confidence: 99%

FOSL1 is a novel mediator of endotoxin/lipopolysaccharide-induced pulmonary angiogenic signaling

Nitkin

Sheng

Menden

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Systemic sepsis is a known risk factor for bronchopulmonary dysplasia (BPD) in premature infants, a disease characterized by dysregulated angiogenesis and impaired vascular and alveolar development. We have previoulsy reported that systemic endotoxin dysregulates pulmonary angiogenesis resulting in alveolar simplification mimicking BPD in neonatal mice, but the underlying mechanisms remain unclear. We undertook an unbiased discovery approach to identify novel signaling pathways programming sepsis-induced deviant lung angiogenesis. Pulmonary endothelial cells (EC) were isolated for RNA-Seq from newborn C57BL/6 mice treated with intraperitoneal lipopolysaccharide (LPS) to mimic systemic sepsis. LPS significantly differentially-regulated 269 genes after 6 h, and 1,934 genes after 24 h. Using bioinformatics, we linked 6 h genes previously unknown to be modulated by LPS to 24 h genes known to regulate angiogenesis/vasculogenesis to identify pathways programming deviant angiogenesis. An immortalized primary human lung EC (HPMEC-im) line was generated by SV40 transduction to facilitate mechanistic studies. RT-PCR and transcription factor binding analysis identified FOSL1 (FOS like 1) as a transcriptional regulator of LPS-induced downstream angiogenic or vasculogenic genes. Over-expression and silencing studies of FOSL1 in immortalized and primary HPMEC demonstrated that baseline and LPS-induced expression of ADAM8, CXCR2, HPX, LRG1, PROK2, and RNF213 was regulated by FOSL1. FOSL1 silencing impaired LPS-induced in vitro HPMEC angiogenesis. In conclusion, we identified FOSL1 as a novel regulator of sepsis-induced deviant angiogenic signaling in mouse lung EC and human fetal HPMEC. Bronchopulmonary dysplasia (BPD) is a developmental lung disorder characterized by simplified alveoli and dysmorphic pulmonary vasculature 1-6. BPD affects approximately 40% of infants born at ≤ 28 weeks gestational age with up to 29% mortality 7. Recent studies have found that maternal chorioamnionitis increases the incidence of BPD and perinatal mortality 8 , and postnatal sepsis or pneumonia increases the risk of preterm infants developing BPD 9. While oxygen toxicity, mechanical ventilation, and inflammation are traditional risk factors for the development of BPD, systemic sepsis has emerged as a significant risk factor for BPD 10-13. Systemic sepsis caused by Gram-positive and Gram-negative bacteria is common in premature infants, and is associated with BPD 9,14-16. in addition to airway colonization with Gram negative bacilli correlates with severe BPD 17. However, the mechanisms underlying sepsis-induced neonatal acute lung injury and alveolar remodeling seen in BPD remain understudied 3,18-21. We have previously shown that postnatal systemic lipopolysaccharide (LPS) disrupts lung development in newborn mice, leading to alveolar simplification in a Nox2-dependent manner 1. However, relatively little is known about the impact of LPS on the developing lung vasculature. In human BPD and hyperoxia models of experimental BPD, several researche...

show abstract

Section: Discussionmentioning

confidence: 99%

FOSL1 is a novel mediator of endotoxin/lipopolysaccharide-induced pulmonary angiogenic signaling

Nitkin

Sheng

Menden

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…In our previous study, we injected TALEN mRNAs into embryos forming rnf213a mutant chimera and found that chimeric embryos developed abnormal angiogenesis and circulatory disorder. 17 Nevertheless, chimeric embryos in which cells with different genotype might cause unexpected phenotype. Thus, we further investigated the role of rnf213a in homozygous knockout zebrafish.…”

Section: Discussionmentioning

confidence: 99%

Mutations of RNF213 are responsible for sporadic cerebral cavernous malformation and lead to a mulberry-like cluster in zebrafish

Lin

Liang

Wen

et al. 2020

J Cereb Blood Flow Metab

Self Cite

View full text Add to dashboard Cite

Although familial forms of cerebral cavernous malformation are mainly attributed to three CCM genes ( KRIT1, CCM2 and PDCD10), no mutation is identified in sporadic cerebral cavernous malformation cases with a unique lesion, indicating additional genes for sporadic cerebral cavernous malformation. To screen the candidate genes, we conducted whole exome sequencing in 31 sporadic cerebral cavernous malformation patients and 32 healthy controls, and identified 5 affected individuals carrying 6 heterozygous deleterious mutations in RNF213 but no RNF213 mutation in healthy individuals. To further confirm RNF213 was associated with cerebral cavernous malformation, we generated rnf213a homozygous knockout zebrafish and found mutation of rnf213a in zebrafish led to a mulberry-like cluster of disordered-flow vascular channels which was reminiscent of human cerebral cavernous malformation. In addition, we revealed kbtbd7 and anxa6 were significantly downregulated due to rnf213a mutation through transcriptomic sequencing and RT-qPCR analysis. Based on the mulberry-like phenotype partly rescued by mRNA of kbtbd7 as well as anxa6, we suggested that rnf213a promoted mulberry-like cluster via downregulation of kbtbd7 and anxa6. Altogether, we firstly demonstrate RNF213is a novel candidate gene for sporadic cerebral cavernous malformation and the mutation of rnf213a is responsible for the mulberry-like cluster in zebrafish.

show abstract

“…However, the phenotypes produced through morpholino-mediated knockdown of rnf213 expression in zebrafish may have been affected by off-target effects, and recent studies have found that morpholinos have a high probability of off-target effects [25, 26]. Therefore, we knocked out zebrafish rnf213 via a transcription activator-like effector nuclease and found significant angiogenesis of the intersegmental blood vessels and cerebral blood vessels and small blood vessel stenosis in the F0 generation [27]. By similarly knocking out RNF213, the zebrafish model can partially mimic the MMD phenotype, but mouse models failed to mimic the MMD phenotype, even if the mice were superimposed with hypoxia or immunoadjuvant, suggesting that RNF213 may play different roles in MMD in different species.…”

Section: Rnf213 and MMDmentioning

confidence: 99%

RNF213 Variant Diversity Predisposes Distinct Populations to Dissimilar Cerebrovascular Diseases

Lin

Sheng

2018

BioMed Research International

Self Cite

View full text Add to dashboard Cite

In recent years, the ring finger protein 213 gene (RNF213) has gradually attracted attention, mainly because it has been found that RNF213 c.14429 G>A is associated with moyamoya disease (MMD) in East Asian populations. Recent studies have revealed that RFN213 is not only associated with MMD but is also connected with intracranial major artery stenosis/occlusion (ICASO) and intracranial aneurysm (IA). However, only the relationship between RNF213 c.14429 G>A and ICASO has been confirmed, and whether RNF213 has other mutations related to ICASO remains unclear. RNF213 and IA are currently only confirmed to be correlated in French-Canadian Population and no correlation has been found in the Japanese population. This review summarizes the advances in the associations between RNF213 and different cerebrovascular diseases and highlights that variant diversity of RNF213 may predispose distinct populations to dissimilar cerebrovascular diseases.

show abstract

Mutation of rnf213a by TALEN causes abnormal angiogenesis and circulation defects in zebrafish

Cited by 22 publications

References 30 publications

FOSL1 is a novel mediator of endotoxin/lipopolysaccharide-induced pulmonary angiogenic signaling

FOSL1 is a novel mediator of endotoxin/lipopolysaccharide-induced pulmonary angiogenic signaling

Mutations of RNF213 are responsible for sporadic cerebral cavernous malformation and lead to a mulberry-like cluster in zebrafish

RNF213 Variant Diversity Predisposes Distinct Populations to Dissimilar Cerebrovascular Diseases

Contact Info

Product

Resources

About