ROCK1 Expression is Regulated by TGFβ3 and ALK2 During Valvuloseptal Endocardial Cushion Formation

Sakabe, Masahide; Sakata, Hirokazu; Matsui, Hiroko; Ikeda, Kazuo; Yamagishi, Toshiyuki; Nakajima, Yuji

doi:10.1002/ar.20708

Cited by 10 publications

(8 citation statements)

References 51 publications

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“…During early heart development, endothelial cells in the outflow tract and atrioventricular regions transform into mesenchyme that ultimately becomes endocardial cushion tissue. ROCK1 plays an important role in the regulation of endocardial cell differentiation and migration (Zhao and Rivkees 2004; Sakabe et al 2006) Specifically, ROCK1 is up-regulated at the onset of the epithelial-mesenchyme transition phase in the heart (Sakabe et al 2008). The fact that ROCK1 is up-regulated in both trisomies 18 and 21, and that both valvular and endocardial cushion abnormalities are found in these conditions, is intriguing and suggests a common mechanism.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of cell-free fetal RNA suggests a specific molecular phenotype in trisomy 18

et al. 2010

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Background Trisomy 18 is a common human aneuploidy that is associated with significant perinatal mortality. Unlike the well-characterized “critical region” in trisomy 21 (21q22), there is no corresponding region on chromosome 18 associated with its pathogenesis. The high morbidity and mortality of affected individuals has limited extensive investigations. Objective To better understand the molecular mechanisms underlying the congenital anomalies observed in this condition, we investigated the in utero gene expression profile of second trimester fetuses affected with trisomy 18. Methods Total RNA was extracted from cell-free amniotic fluid supernatant from aneuploid fetuses and euploid controls matched for gestational age and hybridized to Affymetrix U133 Plus 2.0 arrays. Individual differentially-expressed transcripts were obtained by two-tailed t-tests. Over-represented functional pathways among these genes were identified with DAVID and Ingenuity® Pathways Analysis. Results Three hundred fifty-two probe sets representing 251 annotated genes were statistically significantly differentially expressed between trisomy 18 and controls. Only 7 genes (2.8% of the annotated total) were located on chromosome 18, including ROCK1, an up-regulated gene involved in valvuloseptal and endocardial cushion formation. Pathway analysis indicated disrupted function in ion transport, MHCII/T-cell mediated immunity, DNA repair, G-protein mediated signaling, kinases, and glycosylation. Significant down-regulation of genes involved in adrenal development was identified, which may explain both the abnormal maternal serum estriols and the pre and postnatal growth restriction in trisomy 18. Comparison of this gene set to one previously generated for trisomy 21 fetuses revealed only six overlapping differentially-regulated genes. Conclusion This study contributes novel information regarding functional developmental gene expression differences in fetuses with trisomy 18.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of cell-free fetal RNA suggests a specific molecular phenotype in trisomy 18

et al. 2010

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“…We posit that SNRK’s involvement in the two signaling pathways may not be mutually exclusive since both have been implicated in CMs function previously. For example, TGF-β3 and ALK2 regulate ROCK1 expression during valvuloseptal endocardial cushion formation 38 , and up regulation of bone morphogenetic protein-2 (BMP-2), antagonized TGF-β1/ROCK-enhanced cardiac fibrotic signal through activation of Smurf1/Smad6 complex 37 . In this study, we only focused on ROCK because of the overwhelming evidence suggesting ROCK as a cardiovascular risk factor 39 , and its role in cardiovascular physiology and pathophysiology 4 .…”

Section: Discussionmentioning

confidence: 99%

Sucrose Nonfermenting-Related Kinase Enzyme–Mediated Rho-Associated Kinase Signaling is Responsible for Cardiac Function

Cossette¹,

Bhute²,

Bao³

et al. 2016

Circ Cardiovasc Genet

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Background Cardiac metabolism is critical for the functioning of the heart, and disturbance in this homeostasis is likely to influence cardiac disorders or cardiomyopathy. Our lab has previously shown that sucrose non-fermenting related kinase (SNRK) enzyme, which belongs to the AMP-activated kinase (AMPK) family, was essential for cardiac metabolism in mammals. Snrk global homozygous knockout (KO) mice die at postnatal day 0, and conditional deletion of Snrk in cardiomyocytes (Snrk cmcKO) leads to cardiac failure, and death by 8–10 months. Methods and Results We performed additional cardiac functional studies using echocardiography (ECHO), and identified further cardiac functional deficits in Snrk cmcKO mice. NMR-based metabolomics analysis identified key metabolic pathway deficits in SNRK knockdown cardiomyocytes (CMs) in vitro. Specifically, metabolites involved in lipid metabolism and oxidative phosphorylation are altered and perturbations in these pathways can result in cardiac function deficits and heart failure. A phosphopeptide-based proteomic screen identified Rho-associated kinase (ROCK) as a putative substrate for SNRK and mass spec-based fragment analysis confirmed key amino acid residues on ROCK that are phosphorylated by SNRK. Western blot analysis on heart lysates from Snrk cmcKO adult mice and SNRK knockdown CMs showed increased ROCK activity. In addition, in vivo inhibition of ROCK partially rescued the in vivo Snrk cmcKO cardiac function deficits. Conclusions Collectively, our data suggests that SNRK in CMs is responsible for maintaining cardiac metabolic homeostasis, which is mediated in part by ROCK and alteration of this homeostasis influences cardiac function in the adult heart.

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“…We previously reported that ROCK1/2 is expressed in gastrulating cells (Sakata et al. 2007), and TGF‐β signal is able to upregulate the expression of ROCK1 in endocardial cells at the onset of epithelial‐mesenchymal transition in valvuloseptal endocardial cushion formation (Sakabe et al. 2008).…”

Section: Discussionmentioning

confidence: 99%

Nodal signal is required for morphogenetic movements of epiblast layer in the pre‐streak chick blastoderm

et al. 2011

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During axis formation in amniotes, posterior and lateral epiblast cells in the area pellucida undergo a counterrotating movement along the midline to form primitive streak (Polonaise movements). Using chick blastoderms, we investigated the signaling involved in this cellular movement in epithelial-epiblast. In cultured posterior blastoderm explants from stage X to XI embryos, either Lefty1 or Cerberus-S inhibited initial migration of the explants on chamber slides. In vivo analysis showed that inhibition of Nodal signaling by Lefty1 affected the movement of DiI-marked epiblast cells prior to the formation of primitive streak. In Lefty1-treated embryos without a primitive streak, Brachyury expression showed a patchy distribution. However, SU5402 did not affect the movement of DiI-marked epiblast cells. Multi-cellular rosette, which is thought to be involved in epithelial morphogenesis, was found predominantly in the posterior half of the epiblast, and Lefty1 inhibited the formation of rosettes. Three-dimensional reconstruction showed two types of rosette, one with a protruding cell, the other with a ventral hollow. Our results suggest that Nodal signaling may have a pivotal role in the morphogenetic movements of epithelial epiblast including Polonaise movements and formation of multi-cellular rosette.

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ROCK1 Expression is Regulated by TGFβ3 and ALK2 During Valvuloseptal Endocardial Cushion Formation

Cited by 10 publications

References 51 publications

Transcriptomic analysis of cell-free fetal RNA suggests a specific molecular phenotype in trisomy 18

Transcriptomic analysis of cell-free fetal RNA suggests a specific molecular phenotype in trisomy 18

Sucrose Nonfermenting-Related Kinase Enzyme–Mediated Rho-Associated Kinase Signaling is Responsible for Cardiac Function

Nodal signal is required for morphogenetic movements of epiblast layer in the pre‐streak chick blastoderm

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