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Thư viện số Văn Lang: Etiology and Morphogenesis of Congenital Heart Disease: From Gene Function and Cellular Interaction to Morphology

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Nguyễn Gia Hào

Academic year: 2023

Chia sẻ "Thư viện số Văn Lang: Etiology and Morphogenesis of Congenital Heart Disease: From Gene Function and Cellular Interaction to Morphology"

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At E7.5, the anterior part of the lateral plate mesoderm is identified as the heart fields, the direct source of the heart tube [1, 4]. Given the anatomical two heart field paradigm, CPCs are classified into FHF CPCs and SHF CPCs (Fig. 10.1b). During reverse transcription, Moloney murine leukemia virus reverse transcriptase adds a short poly C tail to the 30′ end of the first-strand cDNA.

The orderly assignment of mesodermal cells to the extraembryonic structures and the anteroposterior axis during gastrulation of the mouse embryo.

Fig. 10.1 The heart development. (a) Schematic illustration of the heart development. The progeny of FHF is indicated by red and that of SHF is by blue
Fig. 10.1 The heart development. (a) Schematic illustration of the heart development. The progeny of FHF is indicated by red and that of SHF is by blue

Introduction

Increased Meis1 expression Following MI at P7 after 7 days B. Expression profile of Meis1 in the neonatal mouse heart C. 11.1 Expression profile of Meis1 in postnatal heart. a) qRT-PCR showing increased expression of Meis1 at postnatal day 7 (P7), a time point coinciding with cell cycle arrest of cardiomyocytes.

Fig. 11.1 Expression profile of Meis1 in postnatal heart. (a) qRT–PCR showing increased expression of Meis1 at postnatal day 7 (P7), a time point that coincides with cell cycle arrest of cardiomyocytes
Fig. 11.1 Expression profile of Meis1 in postnatal heart. (a) qRT–PCR showing increased expression of Meis1 at postnatal day 7 (P7), a time point that coincides with cell cycle arrest of cardiomyocytes

Results

This is supported by a decrease in the number of mitotic cardiomyocytes in Meis1 (OE) neonatal hearts (Fig.11.3g). Finally, Meis1 OE in cardiomyocytes resulted in up-regulation of CDK inhibitors, most significantly p21 (Cdkn1a) (Fig. 11.3k).

Fig. 11.2 Cardiomyocyte proliferation at P14 following Meis1 deletion. (a) Schematic of Meis1 floxed allele
Fig. 11.2 Cardiomyocyte proliferation at P14 following Meis1 deletion. (a) Schematic of Meis1 floxed allele

Future Direction and Clinical Implications

Images or other third-party material in this chapter are covered under a Creative Commons license for the work, unless otherwise noted in the credit line; if such material is not covered by a Creative Commons license for the work and such action is not permitted by law, users will need to obtain permission from the licensee to duplicate, adapt or reproduce the material. Meis1 regulates cardiomyocyte cell cycle arrest through transcriptional activation of CDKIs, the INK4b–ARF–INK4a locus, and p21, and indirectly through a number of other cell cycle regulators. Cardiomyocyte cell cycle control and growth assessment in vivo - analysis based on cardiomyocyte nuclei.

The Meis1 homeodomain protein is essential for definitive hematopoiesis and vascular patterning in the mouse embryo. Rb and p130 control cell cycle gene silencing to maintain the postmitotic phenotype in cardiac myocytes. The heart is the first organ to develop in the embryo, and its formation is an extremely regulated process.

Inherited mutations in genes necessary for heart development can cause congenital heart disease (CHD), manifested in the newborn or in the adult. Recent work has shown that endocardial Notch activity orchestrates early events, as well as ventricular chamber patterning and morphogenesis in the mouse, and that inactivating mutations in the NOTCH pathway regulator MIND BOMB-1 (MIB1) cause left ventricular noncompaction (LVNC), a cardiomyopathy of poorly understood etiology. Here, we review these data that shed some light on the etiology of LVNC that, at least in the case of that caused by MIB1 mutations, has a developmental basis.

Fig. 11.5 Proposed model of cardiomyocyte cell cycle regulation by Meis1. Meis1 regulates cardiomyocyte cell cycle arrest through transcriptional activation of CDKIs, INK4b–ARF–INK4a locus, and p21, as well as indirectly through a number of other cell cycl
Fig. 11.5 Proposed model of cardiomyocyte cell cycle regulation by Meis1. Meis1 regulates cardiomyocyte cell cycle arrest through transcriptional activation of CDKIs, INK4b–ARF–INK4a locus, and p21, as well as indirectly through a number of other cell cycl

Introduction

At E7.0 cardiac progenitors (yellow) migrate to the center of the embryo to form the heart tube and at E7.5 two heart fields can be distinguished: the first heart field (FHF; yellow) and the second heart field (SHF; green). At E9.0, the tube loops and by E9.5, has four anatomically distinct regions: atrium, atrioventricular canal (AVC), ventricle (V) and outflow tract (OFT).

Fig. 12.1 Overview of early heart development. (a) Ventral views of the developing mouse embryo
Fig. 12.1 Overview of early heart development. (a) Ventral views of the developing mouse embryo

Left Ventricular Non-compaction (LVNC)

The NOTCH Signaling Pathway

In mammals, the Notch ligands belong to the Delta-like (Dll1, Dll3 and Dll4) and Jagged (Jag1 and Jag2) families. The Notch ligands Delta and Jagged are bound to the membrane of the signaling cell. On their way to the plasma membrane, the Notch receptors are modified in their extracellular domains (NECD) by Fringe.

NICD translocates to the nucleus and forms a transcriptional activation complex together with RBPJK and MAML that activates transcription of target genes, including HesandHeyt encoding transcriptional repressors. The glycosyl-transferase fringe can modify the EGF-like domain in the NECD of the receptor by adding O-fucose glycans [5] (Fig.12.2). Mib1 binds to two families of Notch ligands and is a regulatory point of the signaling pathway in the cell.

Immediately afterwards, γ-secretase/presenilin cleaves the receptor at the third site and releases NICD in the cytoplasm of the recipient cell [26] (Figure 12.2). NICD translocates to the nucleus, where it binds to the transcription factor CSL or RBPJK via the RAM23 domain [ 32 ]. In the absence of Notch signaling activation, RBPJK is bound to nuclear corepressors that repress gene expression.

NOTCH in Ventricular Chamber Development

EphB4 signaling in the endocardium, which in turn is required for Nrg1 expression in this tissue. Likewise, loss or reduced expression of Hey1, Hey3, and EphrinB2 in compact myocardial vessels suggested that coronary artery development was defective. Proliferation analysis revealed increased proliferation of trabecular cardiomyocytes in the hearts of E15.5 Mib1flox;cTnT-Cre embryos, suggesting this as the cause of enlarged rather than compacted trabeculae in these mutants.

The expression of genes involved in the differentiation of cardiac endothelium/endocardium and cardiomyocytes and coronary vasculogenesis was altered. RNA-Seq data also confirmed the in situ hybridization analysis and demonstrated that Mib1 inactivation in the myocardium disrupts the differentiation and maturation of cardiac endothelial cells and cardiomyocytes. The second mutation was a heterozygous C to T transition from nucleotide 1587 in MIB1 exon 11 (causing a premature stop codon instead of arginine at position 530 in the MIB1 ankyrin repeat region, the p.Arg530X mutation).

Finally, to examine the effect of these mutant MIB1 variants in vivo, their mRNAs were microinjected into zebrafish embryos expressing GFP in the developing myocardium. Regarding the role of Mib1 in ventricular chamber development, we proposed that myocardial Mib1 activity enables Jag1-mediated activation of Notch1 in the endocardium to maintain patterning, maturation and compaction of trabeculae [22] and (Figure 12.4). Disruption of Mib1-mediated signaling in the myocardium disrupts trabeculae maturation and patterning, arrests myocardial chamber development, and results in LVNC (Figure 12.4).

Future Directions and Clinical Implications

In the case of p.Arg530X, this will be due to haploinsufficiency caused by insufficient synthesis of WT MIB1 protein; in the case of p.Val934Phe, this would be due to a dominant-negative effect of the mutant protein, which down-titrates the amount of functional WT MIB1 dimers through heterotypic or homotypic interactions. In wild-type (WT) embryos, ubiquitylation of Jag1 (and another ligand?) by Mib1 in the myocardium allows Notch1 activation in the endocardium. Identification of a rare congenital anomaly of the myocardium by two-dimensional echocardiography: persistence of isolated myocardial sinusoids.

Synergistic roles of neuregulin-1 and insulin-like growth factor-I in activation of the phosphatidylinositol 3-kinase pathway and cardiac chamber morphogenesis. Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H). The epicardium has several essential functions in the development of cardiac architecture and differentiation of the myocardium in vertebrates.

We revealed a novel function of the epicardium in species with partial or complete ventricular septation including reptiles, birds and mammals. We find that the primitive ventricle of early embryos becomes separated by folding and fusion of the anterior ventricular wall, trapping the epicardium at its core. This 'folding septum', as we propose to call it, develops in lizards, snakes and turtles into the horizontal septum and, in the other taxa examined, into the folding part of the interventricular septum.

Fig. 12.4 Proposed mechanism of Notch function in trabecular maturation and compaction
Fig. 12.4 Proposed mechanism of Notch function in trabecular maturation and compaction

Introduction

In our effort to uncover homologies between the various components of the septum, we draw perspectives on the development of ventricular septal defects in humans.

Septum Components in the Completely Septated Heart

The Presence of the Epicardium in Amniotes

The Epicardium in the Avian Heart

The fold septum (FS) contains quail-derived endothelial cells stained with the QH1 antibody (brown), whereas the inlet septum (IS) is practically negative. Note the decreased number of epicardial cells and EPDCs (brown in this WT1 stain) and the thin fold septum in the mutant. At stage 31, the dye was completely embedded in the fold septum as a narrow fluorescent strip (Fig. 13.5) markedly close to the right ventricular side of the septum, indicating a less extensive right ventricular contribution to the septum [10].

Fig 13.3 (a, b) Quail-chicken chimeras from the anterior position. The folding septum (FS) harbours quail-derived endothelial cells stained with the QH1 antibody (brown), whereas the inlet septum (IS) is virtually negative
Fig 13.3 (a, b) Quail-chicken chimeras from the anterior position. The folding septum (FS) harbours quail-derived endothelial cells stained with the QH1 antibody (brown), whereas the inlet septum (IS) is virtually negative

Disturbance of the Epicardium

Septum Components in Reptilian Hearts

Tbx5 Expression Patterns

Discussion

It was generally agreed that the septal band belonged to the primary septum, being the anterior or, as we now refer to it, the fold component of the septum, but we demonstrated that it belongs to the posterior inlet septum. From this we postulate that the embryonic ventricle of birds and mammals (homologous to the cavum dorsale of reptiles, which is the cavum arteriosum and venosum combined) gives rise to both the left ventricle and the inlet to the right ventricle. This is an indication that the inlet septum in its entirety originates from the wall of the primitive ventricle, cavum dorsale.

In the right ventricle, the boundary of the inlet septum is determined by the septal band, which is not present in the left ventricle, so that the boundary between the inlet and folding septum is less well defined here. Note: The development of the membranous septum and outflow tract septum has not been specifically addressed in this study. Interestingly, elephants and some relatives including manatees show a very deep anterior interventricular sulcus [10]. The anatomy of the right ventricular septal band and the attachment of the tricuspid ischordae tendineae suggest an impaired folding mechanism resulting in the maintenance of an early embryonic state, also known as neoteny.

In conclusion, we investigated an evo-devo context for the hitherto overlooked role of the epicardium in septation and elucidated complex homologies in amniotes of the ventricular septum to understand clinical disorders of the heart in humans. Open Access This chapter is distributed under the terms of the Creative Commons Attribution-Noncommercial 2.5 License (http://creativecommons.org/licenses/by-nc/2.5/) which prohibits any non-commercial use, distribution, and reproduction on any medium, provided that the original author(s) and source are credited. Congenital hypothyroidism (CH) is one of the most common diseases of the endocrine system in newborns.

Fig. 15.1 Proposed mechanism for the role of autophagy in C2C12 cell differentiation.
Fig. 15.1 Proposed mechanism for the role of autophagy in C2C12 cell differentiation.

Hình ảnh

Fig. 10.1 The heart development. (a) Schematic illustration of the heart development. The progeny of FHF is indicated by red and that of SHF is by blue
Table 10.1 Methods of single-cell transcriptomics
Fig. 10.2 Overview of the methods of single-cell transcriptomics. (a) Poly A tailing (Kurimoto’s, Tang’s, Boulette’s protocol and Quartz-seq), (b) SMART-seq, (c) CEL-seq
Fig. 11.1 Expression profile of Meis1 in postnatal heart. (a) qRT–PCR showing increased expression of Meis1 at postnatal day 7 (P7), a time point that coincides with cell cycle arrest of cardiomyocytes
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