Cardiac looping and the vertebrate left-right axis: antagonism of left-sided Vg1 activity by a right-sided ALK2-dependent BMP pathway

Development ◽  
1999 ◽  
Vol 126 (23) ◽  
pp. 5195-5205 ◽  
Author(s):  
A.F. Ramsdell ◽  
H.J. Yost
Keyword(s):  
Signaling Pathway ◽  
Expression Patterns ◽  
Ectopic Expression ◽  
Xenopus Embryo ◽  
Receptor Expression ◽  
Heart Tube ◽  
Cardiac Morphogenesis ◽  
Heart Looping ◽  
Bmp Pathway ◽  
The Right

The rightward looping of the primary heart tube is dependent upon upstream patterning events that establish the vertebrate left-right axis. In Xenopus, a left-sided Vg1 signaling pathway has been implicated in instructing cells to adopt a ‘left-sided identity’; however, it is not known whether ‘right-sided identity’ is acquired by a default pathway or by antagonism of Vg1 signaling. Here, we propose that an antagonistic, BMP/ALK2/Smad-mediated signaling pathway is active on the right side of the Xenopus embryo. Truncated ALK2 receptor expression on the right side of the blastula elicits heart reversals and altered nodal expression. Consistent with these findings, constitutively active ALK2 (CA-ALK2) receptor expression on the left side of the blastula also elicits heart reversals and altered nodal expression. Coexpression of CA-ALK2 with mature Vg1 ligand results in predominantly left-sided nodal expression patterns and normal heart looping, demonstrating that the ALK2 pathway can ‘rescue’ left-right reversals that otherwise occur following right-sided misexpression of mature Vg1 ligand alone. Results with chimeric precursor proteins indicate that the mature domain of BMP ligands can mimic the ability of the ALK2 signaling pathway to antagonize the Vg1 pathway. Consistent with the observed antagonism between BMP and Vg1 ligands, left-sided ectopic expression of Xolloid results in heart reversals. Moreover, ectopic expression of Smad1 or Smad7 identified two downstream modulators of the BMP/ALK2 signaling pathway that also can regulate cardiac orientation. Collectively, these results define a BMP/ALK2-mediated pathway on the right side of the Xenopus embryo and, moreover, suggest that left-right patterning preceding cardiac morphogenesis involves the activation of two distinct and antagonistic, left- and right-sided TGF(beta)-related signaling pathways.

Thylacine 1 is expressed segmentally within the paraxial mesoderm of the Xenopus embryo and interacts with the Notch pathway

Development ◽  
1998 ◽  
Vol 125 (11) ◽  
pp. 2041-2051 ◽  
Author(s):  
D.B. Sparrow ◽  
W.C. Jen ◽  
S. Kotecha ◽  
N. Towers ◽  
C. Kintner ◽  
...  
Keyword(s):  
Expression Patterns ◽  
Ectopic Expression ◽  
Notch Pathway ◽  
Notch Signalling ◽  
Xenopus Embryo ◽  
Paraxial Mesoderm ◽  
Marker Genes ◽  
Transcription Activator ◽  
Presomitic Mesoderm ◽  
Helix Loop Helix

The presomitic mesoderm of vertebrates undergoes a process of segmentation in which cell-cell interactions mediated by the Notch family of receptors and their associated ligands are involved. The vertebrate homologues of Drosophila Δ are expressed in a dynamic, segmental pattern within the presomitic mesoderm, and alterations in the function of these genes leads to a perturbed pattern of somite segmentation. In this study we have characterised Thylacine 1 which encodes a basic helix-loop-helix class transcription activator. Expression of Thylacine is restricted to the presomitic mesoderm, localising to the anterior half of several somitomeres in register with domains of X-Delta-2 expression. Ectopic expression of Thylacine in embryos causes segmentation defects similar to those seen in embryos in which Notch signalling is altered, and these embryos also show severe disruption in the expression patterns of the marker genes X-Delta-2 and X-ESR5 within the presomitic mesoderm. Finally, the expression of Thylacine is altered in embryos when Notch signalling is perturbed. These observations suggest strongly that Thylacine 1 has a role in the segmentation pathway of the Xenopus embryo, by interacting with the Notch signalling pathway.

Development of left/right handedness in the chick heart

Development ◽  
1992 ◽  
Vol 115 (4) ◽  
pp. 1071-1078 ◽  
Author(s):  
C. Hoyle ◽  
N.A. Brown ◽  
L. Wolpert
Keyword(s):  
Chick Embryos ◽  
Heart Tube ◽  
Left Hand ◽  
Right Hand ◽  
Precardiac Mesoderm ◽  
Heart Looping ◽  
Chick Heart ◽  
The Stability ◽  
The Right ◽  
Almost All

The chick heart tube develops from the fusion of the right and left areas of precardiac mesoderm and in almost all cases loops to the embryo's right-hand side. We have investigated whether any intrinsic difference exists in the right and left areas of precardiac mesoderm, that influences the direction of looping of the heart tube. Chick embryos incubated to stages 4,5 and 6 were cultured by the New method. Areas of precardiac mesoderm were exchanged between donor and host embryos of the same stage and different stages to form control, double-right and double-left sided embryos. Overall, double-right sided embryos formed many more left-hand loops than double-left sided embryos. At stages 4 and 5 a small percentage of double-right embryos formed left-hand loops (13%) whereas at stage 6 almost 50% of hearts had left-hand loops. Control embryos formed right-hand loops in 97% of cases. The stability of right-hand heart looping by double-left sided embryos, may be related to the process of ‘conversion’, whereas the direction of looping by double-right sided embryos has become randomised. There is some indication that an intrinsic change occurred in the precardiac mesoderm between stages 5 and 6 that later influenced the direction of looping of the heart tube. The direction of body turning is suggested to be linked to the direction of heart looping.

Finite Element Modeling of the Tubular Embryonic Chick Heart With Smoothed Surfaces and Contact With Splanchnopleure Membrane

2009 ◽  
Author(s):  
Jiang Yao ◽  
Jonathan M. Young ◽  
Benjamen A. Filas ◽  
Nils Klinkenberg ◽  
Jincheng Wang ◽  
...  
Keyword(s):  
Finite Element ◽  
Cardiac Development ◽  
Element Model ◽  
Ventral Surface ◽  
Heart Beat ◽  
Nonlinear Material ◽  
Heart Tube ◽  
Heart Looping ◽  
Chick Heart ◽  
The Right

During cardiac development, the initially straight heart tube bends ventrally and rotates towards the right side of the embryo. The biomechanical mechanism of cardiac looping is still unclear, but it has been hypothesized to be related to the unbalanced forces in the left and right omphalomesenteric veins (OVs) generated by cytoskeletal contraction and cell migration, as well as contact with the Splanchnopleure (SPL), a membrane which is located at the ventral surface of the heart and wraps around the OV at the anterior intestinal portal (AIP) [1]. To test this hypothesis, a computational model is a powerful tool. The objective of this study is to generate a finite element model (FEM) with realistic geometry of the tubular heart with the OVs in its caudal ends, which contacts with the SPL. In alternative to the voxel based model, as explored by Young et al. [2], we study issues related to a model with smoothed surfaces, and its capacity in dealing with nonlinear material, large deformation and contact. Although heart looping proceeds normally without pressure generated from heart beat [3], we applied an internal pressure to test the model.

scholarly journals PDGF signaling directs cardiomyocyte movement toward the midline during heart tube assembly

2016 ◽  
Author(s):  
Joshua Bloomekatz ◽  
Reena Singh ◽  
Owen W.J. Prall ◽  
Ariel C. Dunn ◽  
Megan Vaughan ◽  
...  
Keyword(s):  
Essential Role ◽  
Ectopic Expression ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Heart Tube ◽  
Cardiac Morphogenesis ◽  
Factor Receptor Alpha ◽  
Pdgf Signaling ◽  
Tube Assembly ◽  
Cardiac Fusion

AbstractCommunication between neighboring tissues plays a central role in guiding organ morphogenesis. During heart tube assembly, interactions with the adjacent endoderm control the medial movement of cardiomyocytes, a process referred to as cardiac fusion. However, the molecular underpinnings of this endodermal-myocardial relationship remain unclear. Here, we show an essential role for platelet-derived growth factor receptor alpha (Pdgfra) in directing cardiac fusion. In both zebrafish and mouse, mutation of pdgfra inhibits cardiac fusion and can lead to cardia bifida. Timelapse analysis of individual cardiomyocyte trajectories reveals misdirected cells in zebrafish pdgfra mutants, suggesting that PDGF signaling steers cardiomyocytes toward the midline. Intriguingly, the ligand pdgfaa is expressed in the endoderm medial to the pdgfra-expressing myocardial precursors. Ectopic expression of pdgfaa interferes with cardiac fusion, consistent with an instructive role for PDGF signaling. Together, these data uncover a novel mechanism through which endodermal-myocardial communication guides the cell movements that initiate cardiac morphogenesis.IMPACT STATEMENTStudies in zebrafish and mouse implicate the PDGF signaling pathway in the communication between the endoderm and the myocardium that drives medial myocardial movement and thereby initiates cardiac morphogenesis.

scholarly journals Platelet-derived growth factor (PDGF) signaling directs cardiomyocyte movement toward the midline during heart tube assembly

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Joshua Bloomekatz ◽  
Reena Singh ◽  
Owen WJ Prall ◽  
Ariel C Dunn ◽  
Megan Vaughan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Ectopic Expression ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Heart Tube ◽  
Cardiac Morphogenesis ◽  
Factor Receptor Alpha ◽  
Pdgf Signaling ◽  
Tube Assembly ◽  
Cardiac Fusion

Communication between neighboring tissues plays a central role in guiding organ morphogenesis. During heart tube assembly, interactions with the adjacent endoderm control the medial movement of cardiomyocytes, a process referred to as cardiac fusion. However, the molecular underpinnings of this endodermal-myocardial relationship remain unclear. Here, we show an essential role for platelet-derived growth factor receptor alpha (Pdgfra) in directing cardiac fusion. Mutation of pdgfra disrupts heart tube assembly in both zebrafish and mouse. Timelapse analysis of individual cardiomyocyte trajectories reveals misdirected cells in zebrafish pdgfra mutants, suggesting that PDGF signaling steers cardiomyocytes toward the midline during cardiac fusion. Intriguingly, the ligand pdgfaa is expressed in the endoderm medial to the pdgfra-expressing myocardial precursors. Ectopic expression of pdgfaa interferes with cardiac fusion, consistent with an instructive role for PDGF signaling. Together, these data uncover a novel mechanism through which endodermal-myocardial communication can guide the cell movements that initiate cardiac morphogenesis.

The role of an endogenous PKA inhibitor, PKIα, in organizing left-right axis formation

Development ◽  
2001 ◽  
Vol 128 (13) ◽  
pp. 2509-2515
Author(s):  
Minoru Kawakami ◽  
Nobuki Nakanishi
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Ectopic Expression ◽  
The Body ◽  
Specific Gene ◽  
Axis Formation ◽  
Lateral Plate ◽  
Heart Looping ◽  
Dependent Protein ◽  
The Right

Protein kinase inhibitor (PKI) is an endogenous inhibitor of cAMP-dependent protein kinase A (PKA). We have found that the α-isoform of PKI (PKIα) is asymmetrically expressed along the left-right (L-R) axis in chick embryos. At stage 6, PKIα is expressed on the right side of the node, and this asymmetric expression continues until stage 7+. After stage 8, PKIα expression returns symmetric. Treatment of embryos with antisense PKIα oligonucleotides increased the incidence of reversed heart looping. Antisense oligonucleotides also induced ectopic expression of the left-specific genes Nodal and Pitx2, and suppressed the expression of the right-specific gene SnR in the right lateral plate mesoderm. Similarly, treatment with PKA activators forskolin and Sp-cAMPs resulted in both reversed heart looping and bilateral expression of Nodal. Ectopic activin induced PKIα on the left side of the node, while ectopic Shh and anti-Shh antibody had no effect on PKIα expression. Taken together, these data suggest that PKIα induced by an activin-like molecule, through the inhibition of PKA activity, suppresses the Nodal-Pitx2 pathway on the right side of the body.

Left-right asymmetry of a nodal-related gene is regulated by dorsoanterior midline structures during Xenopus development

Development ◽  
1997 ◽  
Vol 124 (8) ◽  
pp. 1465-1472 ◽  
Author(s):  
J.L. Lohr ◽  
M.C. Danos ◽  
H.J. Yost
Keyword(s):  
Signaling Pathway ◽  
Expression Patterns ◽  
Large Population ◽  
Related Gene ◽  
Lateral Plate ◽  
Dorsal Midline ◽  
Cardiac Looping ◽  
Organ Systems ◽  
Left Right Asymmetry ◽  
The Right

Development of asymmetry along the left-right axis is a critical step in the formation of the vertebrate body plan. Disruptions of normal left-right patterning are associated with abnormalities of multiple organ systems, including significant congenital heart disease. The mouse nodal gene, and its homologues in chick and Xenopus, are among the first genes known to be asymmetrically expressed along the left-right axis before the development of organ asymmetry. Alterations in the expression pattern of mouse nodal and the chick homologue (cNR-1) have been associated with defects in the development of left-right asymmetry and cardiac looping (Levin, M., Johnson, R. L., Stern, C. D., Kuehn, M. and Tabin, C. (1995) Cell 82, 803–814; Collignon, J., Varlet, I. and Robertson, E. J. (1996) Nature 381, 155–158; Lowe, L. A., Supp, D. M., Sampath, K., Yokoyama, T., Wright, C. V. E., Potter, S. S., Overbeek, P. and Kuehn, M. R. (1996) Nature 381, 158–161). Here, we show that the normal expression patterns of the Xenopus nodal-related gene (Xnr-1) are variable in a large population of embryos and that Xnr-1 expression is altered by treatments that perturb normal left-right development. The incidence of abnormal Xnr-1 expression patterns correlates well with cardiac reversal rates in both control and experimentally treated Xenopus embryos. Furthermore, dorsal midline structures, including notochord and/or hypochord and neural floorplate, regulate Xnr-1 expression prior to the specification of cardiac left-right orientation by repression of Xnr-1 expression in the right lateral plate mesoderm during closure of the neural tube. The correlation of Xnr-1 expression and orientation of cardiac looping suggests that Xnr-1 is a component of the left-right signaling pathway required for the specification of cardiac orientation in Xenopus, and that dorsal midline structures normally act to repress the signaling pathway on the right side of the embryo.

scholarly journals Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Robert L. Hollis ◽  
Barbara Stanley ◽  
John P. Thomson ◽  
Michael Churchman ◽  
Ian Croy ◽  
...  
Keyword(s):  
High Risk ◽  
Ovarian Carcinoma ◽  
Expression Patterns ◽  
Parp Inhibitors ◽  
Receptor Expression ◽  
Cancer Type ◽  
Sequencing Data ◽  
Molecular Features ◽  
Endometrioid Ovarian Carcinoma ◽  
Molecular Landscape

AbstractEndometrioid ovarian carcinoma (EnOC) is an under-investigated ovarian cancer type. Recent studies have described disease subtypes defined by genomics and hormone receptor expression patterns; here, we determine the relationship between these subtyping layers to define the molecular landscape of EnOC with high granularity and identify therapeutic vulnerabilities in high-risk cases. Whole exome sequencing data were integrated with progesterone and oestrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathological assessment, revealing dominant clinical and molecular features in the resulting integrated subtypes. We demonstrate significant correlation between subtyping approaches: PR-high (PR + /ER + , PR + /ER−) cases were predominantly CTNNB1-mutant (73.2% vs 18.4%, P < 0.001), while PR-low (PR−/ER + , PR−/ER−) cases displayed higher TP53 mutation frequency (38.8% vs 7.3%, P = 0.001), greater genomic complexity (P = 0.007) and more frequent copy number alterations (P = 0.001). PR-high EnOC patients experience favourable disease-specific survival independent of clinicopathological and genomic features (HR = 0.16, 95% CI 0.04–0.71). TP53 mutation further delineates the outcome of patients with PR-low tumours (HR = 2.56, 95% CI 1.14–5.75). A simple, routinely applicable, classification algorithm utilising immunohistochemistry for PR and p53 recapitulated these subtypes and their survival profiles. The genomic profile of high-risk EnOC subtypes suggests that inhibitors of the MAPK and PI3K-AKT pathways, alongside PARP inhibitors, represent promising candidate agents for improving patient survival. Patients with PR-low TP53-mutant EnOC have the greatest unmet clinical need, while PR-high tumours—which are typically CTNNB1-mutant and TP53 wild-type—experience excellent survival and may represent candidates for trials investigating de-escalation of adjuvant chemotherapy to agents such as endocrine therapy.

Sign in / Sign up

Export Citation Format

Share Document