Gene‐targeted deletion in mice of the <i>Ets</i>−<i>1</i> transcription factor, a candidate gene in the Jacobsen syndrome kidney “critical region,” causes abnormal kidney development

Ye, Maoqing; Xu, Lixin; Fu, Mengxia; Chen, Dongrui; Mattina, Teresa; Zufardi, Orsetta; Rossi, Elena; Bush, Kevin T.; Nigám, Sanjay K.; Grossfeld, Paul

doi:10.1002/ajmg.a.40481

Cited by 3 publications

(4 citation statements)

References 27 publications

(43 reference statements)

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“…1 Combined studies in humans and genetically engineered mice implicate the loss of the ETS1 (E26 transformation specific 1) transcription factor as the cause of CHDs and several other congenital defects in JBS. [11][12][13] ETS1 is a member of the ETS family of transcription factors. This family of transcription factors has important roles in a wide range of biological functions, including the regulation of cellular growth and differentiation as well as in organ development, vascular development and angiogenesis, and in the regulation of vascular inflammation and remodeling.…”

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confidence: 99%

Endothelial Loss of ETS1 Impairs Coronary Vascular Development and Leads to Ventricular Non-Compaction

Wang

Lin

et al. 2022

Circulation Research

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Rationale: Jacobsen syndrome is a rare chromosomal disorder caused by deletions in the long arm of human chromosome 11, resulting in multiple developmental defects including congenital heart defects. Combined studies in humans and genetically engineered mice implicate that loss of ETS1 (E26 transformation specific 1) is the cause of congenital heart defects in Jacobsen syndrome, but the underlying molecular and cellular mechanisms are unknown. Objective: To determine the role of ETS1 in heart development, specifically its roles in coronary endothelium and endocardium and the mechanisms by which loss of ETS1 causes coronary vascular defects and ventricular noncompaction. Methods and Results: ETS1 global and endothelial-specific knockout mice were used. Phenotypic assessments, RNA sequencing, and chromatin immunoprecipitation analysis were performed together with expression analysis, immunofluorescence and RNAscope in situ hybridization to uncover phenotypic and transcriptomic changes in response to loss of ETS1. Loss of ETS1 in endothelial cells causes ventricular noncompaction, reproducing the phenotype arising from global deletion of ETS1. Endothelial-specific deletion of ETS1 decreased the levels of Alk1, Cldn5, Sox18, Robo4, Esm1, and Kdr, 6 important angiogenesis-relevant genes in endothelial cells, causing a coronary vasculature developmental defect in association with decreased compact zone cardiomyocyte proliferation. Downregulation of ALK1 expression in endocardium due to the loss of ETS1, along with the upregulation of TGF (transforming growth factor)-β1 and TGF-β3, occurred with increased TGFBR2/TGFBR1/SMAD2 signaling and increased extracellular matrix expression in the trabecular layer, in association with increased trabecular cardiomyocyte proliferation. Conclusions: These results demonstrate the importance of endothelial and endocardial ETS1 in cardiac development. Delineation of the gene regulatory network involving ETS1 in heart development will enhance our understanding of the molecular mechanisms underlying ventricular and coronary vascular developmental defects and will lead to improved approaches for the treatment of patients with congenital heart disease.

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Endothelial Loss of ETS1 Impairs Coronary Vascular Development and Leads to Ventricular Non-Compaction

Wang

Lin

et al. 2022

Circulation Research

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“…Using KO ETS1 mice, Ye et al (2018) identified an overrepresentation of structural kidney defects, including unilateral duplicated ureters, duplicated kidneys, and unilateral renal hypoplasia. However, KO mice do not show complete dominance.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study and sequence similarity analysis for unilateral renal agenesis using heterogeneous stock rats undercovers theKITgene andAHR,ATF3,GATA3,HNF1B,POU2F2, andTFCP2transcription factors as potential candidates to explain incomplete penetrance

Leal-Gutiérrez,

Munro,

Chen

et al. 2023

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Human unilateral renal agenesis is a congenital urinary tract malformation. Affected individuals have only one kidney, which is often an asymptomatic developmental defect. A total of 5,585 male and female HS rats were assessed for unilateral renal agenesis and genotyped for 3,513,321 markers. The R package SAIGEgds was used for the association analysis. The adjusted p-value threshold for the association analysis determined by permutation was equal to 5.6 (-log10). Two additional datasets were used as validation tests. Population two included 1,577 rats genotyped for 7,425,889 markers and a case-control imbalance equal to 1:174; population three included 1,407 rats, genotyped for 254,932 markers and case-control ratio equal to 1:38. The python package GxTheta was used to perform a polygenic epistasis analysis for the analyzed HS rat population. A founder haplotype mosaic determination was performed using the R package QTL2. Associated regions were selected for further analysis, including long-read PacBio sequencing for founder individuals and a founder haplotype prediction test. A similarity analysis at a genomic level and for loci encoding transcription factors predicted to interact with selected sequences inside the associated loci were accomplished. A total of 1,181 polymorphisms were associated with URA. All associated polymorphisms were located on chromosome 14 between 32.9 and 36.6 Mb. The most significant polymorphism was chr14:36,411,266, a G/T transversion. The same associated region was identified in population three. Polygenic epistasis was determined as not predominant for the presentation of URA. Based on the haplotype mosaic probability estimation, cases display a higher probability of inheriting the ACI allele. The long-read sequencing analysis showed the presence of an Erv insertion inside the intron one of the KIT gene located inside the associated region. The Erv insertion comprises one Erv sequence and two Ltr sequences located downstream and upstream of the former. No Erv insertion was identified for the founder strain BN. For ACI and HSRA, only one Ltr sequence was identified. One hundred and seven genes encoding TFs that recognize binding sites on the Erv insertion were analyzed for sequence similarity against the reference HSRA. The TF similarity score analysis for the interaction genotype and phenotype showed significance after FDR correction for 20 TFs, including AHR, HNF1B, JUNB, RARG, and RXRA. A mechanism identifying URA as a threshold phenotype is suggested in HS rats. It implies the existence of a minimum threshold for the final number of nephrons and kidney associated structures required for stalling the apoptotic process of the metanephric rudiments. Animals exhibiting a quantitative cumulative defect would express URA, being this malformation identified as a phenotype with decreased penetrance in the assessed population of HS rats. All these processes are described as mediated by KIT and TFs able to interact with sequences of the Erv insertion.

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“…Concrescence may occur during root formation or after the radicular phase of development is completed. From the stages of tooth development, different degrees union of cementum, dentine, and enamel are possible [ 2 ], and the cause of tooth development abnormalities is hyperactivity of odontogenic epithelium [ 9 ]; the failure of the process of degeneration of the residual dental lamina cells leads to further reaction and over-proliferating and eventually develops into supernumerary teeth [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several approaches are available for the treatment of supernumerary concrescence. The treatment can be performed in two means: (a) surgical extraction or (b) maintenance of the asymptomatic tooth and periodic monitoring at least once a year [ 9 ]. In this case, the impacted teeth led to pericoronitis sometimes, and they might cause the absorption and destruction of the distal neck bone in 37#.…”

Section: Discussionmentioning

confidence: 99%

A Rare Case of Concrescence of Mandibular Third Molar and Supernumerary Fourth Molar

Wang

Yang

et al. 2022

Case Reports in Dentistry

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Concrescence reveals a rare developmental anomaly in which two fully formed teeth are joined along the root surfaces by cementum, and generally occurs in maxillary molars, especially in a third molar and a supernumerary tooth. Very few cases have been reported about the concrescence of a third molar and a supernumerary fourth molar. Based on our available knowledge, this case report described a rare presentation in which concrescence is observed between a third molar and a supernumerary fourth molar in the mandible by diagnosing with cone-beam CT and histological examination.

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Gene‐targeted deletion in mice of the Ets−1 transcription factor, a candidate gene in the Jacobsen syndrome kidney “critical region,” causes abnormal kidney development

Cited by 3 publications

References 27 publications

Endothelial Loss of ETS1 Impairs Coronary Vascular Development and Leads to Ventricular Non-Compaction

Endothelial Loss of ETS1 Impairs Coronary Vascular Development and Leads to Ventricular Non-Compaction

Genome-wide association study and sequence similarity analysis for unilateral renal agenesis using heterogeneous stock rats undercovers theKITgene andAHR,ATF3,GATA3,HNF1B,POU2F2, andTFCP2transcription factors as potential candidates to explain incomplete penetrance

A Rare Case of Concrescence of Mandibular Third Molar and Supernumerary Fourth Molar

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