Impairment of endothelial‐mesenchymal transformation during atrioventricular cushion formation in <i>Tmem100</i> null embryos

Mizuta, Ken; Sakabe, Masahide; Hashimoto, Aya; Ioka, Tomoko; Sakai, Chihiro; Okumura, Kazuki; Hattammaru, Miwa; Fujita, Masahide; Araki, Mutsumi; Somekawa, Satoshi; Saito, Yoshihiko; Nakagawa, Osamu

doi:10.1002/dvdy.24216

Cited by 18 publications

(12 citation statements)

References 41 publications

(107 reference statements)

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“…In hepatocellular carcinomas, a tumor suppressor role of TMEM100 by inhibition of proliferation and metastatic spread has been described [56] . In agreement, lack of TMEM100 induces VEGFA expression in myocardial cells [55] . In the HIF2A PGLs, we noticed higher TMEM100 levels and lower VEGFA expression compared with other pseudohypoxic PGLs, in which the opposite pattern was observed.…”

Section: Discussionsupporting

confidence: 68%

“…Of those, TMEM100, LRRC63 , and NPY best qualified as characteristically expressed in HIF2A PGLs. TMEM100 is essential for epithelial to mesenchymal transition [55] , which is required for maturation and migration of neural crest precursors. In hepatocellular carcinomas, a tumor suppressor role of TMEM100 by inhibition of proliferation and metastatic spread has been described [56] .…”

Section: Discussionmentioning

confidence: 99%

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Hypoxia-Inducible Factor 2α Mutation-Related Paragangliomas Classify as Discrete Pseudohypoxic Subcluster

Fliedner

Shankavaram

Marzouca³

et al. 2016

Neoplasia

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Recently, activating mutations of the hypoxia-inducible factor 2α gene (HIF2A/EPAS1) have been recognized to predispose to multiple paragangliomas (PGLs) and duodenal somatostatinomas associated with polycythemia, and ocular abnormalities. Previously, mutations in the SDHA/B/C/D, SDHAF2, VHL, FH, PHD1, and PHD2 genes have been associated with HIF activation and the development of pseudohypoxic (cluster-1) PGLs. These tumors overlap in terms of tumor location, syndromic presentation, and noradrenergic phenotype to a certain extent. However, they also differ especially by clinical outcome and by presence of other tumors or abnormalities. In the present study, we aimed to establish additional molecular differences between HIF2A and non-HIF2A pseudohypoxic PGLs. RNA expression patterns of HIF2A PGLs (n = 6) from 2 patients were compared with normal adrenal medullas (n = 8) and other hereditary pseudohypoxic PGLs (VHL: n = 13, SDHB: n = 15, and SDHD: n = 14). Unsupervised hierarchical clustering showed that HIF2A PGLs made up a separate cluster from other pseudohypoxic PGLs. Significance analysis of microarray yielded 875 differentially expressed genes between HIF2A and other pseudohypoxic PGLs after normalization to adrenal medulla (false discovery rate 0.01). Prediction analysis of microarray allowed correct classification of all HIF2A samples based on as little as three genes (TRHDE, LRRC63, IGSF10; error rate: 0.02). Genes with the highest expression difference between normal medulla and HIF2A PGLs were selected for confirmatory quantitative reverse transcriptase polymerase chain reaction. In conclusion, HIF2A PGLs show a characteristic expression signature that separates them from non-HIF2A pseudohypoxic PGLs. Unexpectedly, the most significantly differentially expressed genes have not been previously described as HIF target genes.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Hypoxia-Inducible Factor 2α Mutation-Related Paragangliomas Classify as Discrete Pseudohypoxic Subcluster

Fliedner

Shankavaram

Marzouca³

et al. 2016

Neoplasia

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“…HAS2 synthesizes the extracellular matrix component hyaluronan, required for endocardial cell EMT (Camenisch et al, 2000). TMEM100 is a transmembrane protein and HEY1 is a transcription factor also required for endocardial cell EMT (Fischer et al, 2007;Mizuta et al, 2015). BMP2 binds to the TGFBR3 cell surface receptor to mediate EMT in chick endocardial cushion explants (Kirkbride et al, 2008).…”

Section: Resultsmentioning

confidence: 99%

Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure

Carpinelli

Vries

Auden

et al. 2020

Disease Models &Amp; Mechanisms

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Cleft lip and palate are common birth defects resulting from failure of the facial processes to fuse during development. The mammalian grainyhead-like (Grhl1-3) genes play key roles in a number of tissue fusion processes including neurulation, epidermal wound healing and eyelid fusion. One family member, Grhl2, is expressed in the epithelial lining of the first pharyngeal arch in mice at embryonic day (E)10.5, prompting analysis of the role of this factor in palatogenesis. Grhl2null mice die at E11.5 with neural tube defects and a cleft face phenotype, precluding analysis of palatal fusion at a later stage of development. However, in the first pharyngeal arch of Grhl2-null embryos, dysregulation of transcription factors that drive epithelialmesenchymal transition (EMT) occurs. The aberrant expression of these genes is associated with a shift in RNA-splicing patterns that favours the generation of mesenchymal isoforms of numerous regulators. Driving the EMT perturbation is loss of expression of the EMT-suppressing transcription factors Ovol1 and Ovol2, which are direct GRHL2 targets. The expression of the miR-200 family of microRNAs, also GRHL2 targets, is similarly reduced, resulting in a 56-fold upregulation of Zeb1 expression, a major driver of mesenchymal cellular identity. The critical role of GRHL2 in mediating cleft palate in Zeb1 −/− mice is evident, with rescue of both palatal and facial fusion seen in Grhl2 −/− ;Zeb1 −/− embryos. These findings highlight the delicate balance between GRHL2/ZEB1 and epithelial/mesenchymal cellular identity that is essential for normal closure of the palate and face. Perturbation of this pathway may underlie cleft palate in some patients.

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“…Because Tmem100 is expressed in endothelial cells and involved in endothelial differentiation (35), it may not be a direct target of Jarid2 in cardiomyocytes. Tmem100 KO mice are embryonic lethal with cardiovascular failure (36). The sarcoplasmic/endoplasmic reticulum Ca 2ϩ -ATPase (SERCA) is a major component of Ca 2ϩ cycling, and reduction of SERCA expression and activity have been linked to diastolic dysfunction in failing hearts (37).…”

Section: Critical Functions Of Jarid2 In the Postnatal Heart Gene Expmentioning

confidence: 99%

Myocardial-specific ablation of Jumonji and AT-rich interaction domain–containing 2 (Jarid2) leads to dilated cardiomyopathy in mice

Cho¹,

Kang

et al. 2019

Journal of Biological Chemistry

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Edited by Qi-Qun Tang Cardiomyopathy is a common myocardial disease that can lead to sudden death. However, molecular mechanisms underlying cardiomyopathy remain unclear. Jumonji and AT-rich interaction domain-containing 2 (Jarid2) is necessary for embryonic heart development, but functions of Jarid2 after birth remain to be elucidated. Here, we report that myocardialspecific deletion of Jarid2 using ␣MHC::Cre mice (Jarid2 ␣MHC) causes dilated cardiomyopathy (DCM) and premature death 6-9 months after birth. To determine functions of Jarid2 in the adult heart and DCM, we analyzed gene expression in the heart at postnatal day (p)10 (neonatal) and 7 months (DCM). Pathway analyses revealed that dysregulated genes in Jarid2 ␣MHC hearts at p10, prior to cardiomyopathy, represented heart development and muscle contraction pathways. At 7 months, down-regulated genes in Jarid2 ␣MHC hearts were enriched in metabolic process and ion channel activity pathways and up-regulated genes in extracellular matrix components. In normal hearts, expression levels of contractile genes were increased from p10 to 7 months but were not sufficiently increased in Jarid2 ␣MHC hearts. Moreover, Jarid2 was also necessary to repress fetal contractile genes such as TroponinI1, slow skeletal type (Tnni1) and Actin alpha 2, smooth muscle (Acta2) in neonatal stages through ErbB2-receptor tyrosine kinase 4 (ErbB4) signaling. Interestingly, Ankyrin repeat domain 1 (Ankrd1) and Neuregulin 1 (Nrg1), whose expression levels are known to be increased in the failing heart, were already elevated in Jarid2 ␣MHC hearts within 1 month of birth. Thus, we demonstrate that ablation of Jarid2 in cardiomyocytes results in DCM and suggest that Jarid2 plays important roles in cardiomyocyte maturation during neonatal stages.

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Impairment of endothelial‐mesenchymal transformation during atrioventricular cushion formation in Tmem100 null embryos

Cited by 18 publications

References 41 publications

Hypoxia-Inducible Factor 2α Mutation-Related Paragangliomas Classify as Discrete Pseudohypoxic Subcluster

Hypoxia-Inducible Factor 2α Mutation-Related Paragangliomas Classify as Discrete Pseudohypoxic Subcluster

Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure

Myocardial-specific ablation of Jumonji and AT-rich interaction domain–containing 2 (Jarid2) leads to dilated cardiomyopathy in mice

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