Elongation of the heart tube occurs with the progressive addition of cells from the pharyngeal mesoderm to the poles of the heart. These progenitor cells, called the second heart field, contribute to the right ventricular and outflow tract myocardium at the arterial pole of the heart and the atrial myocardium at the venous pole. Here we briefly review a selection of recent findings in the field of cardiac second domain biology and discuss the clinical implications of these new studies for our understanding of the etiology of congenital heart defects.
The inducible Cre allele of Hcn4 allowed assessment of the contribution of FHF to the definitive heart. The importance of disturbances in the development of SHF in the etiology of common forms of CHD affecting both poles of the heart is now clear. A logical model of the cardiac gene regulatory network that determines the identity of the first and second heart fields.
Resolving cell lineage contributions to the ventricular conduction system with a Cx40-GFP allele: a dual contribution of the first and second heart fields. Expression of the BMP receptor Alk3 in the second heart field is essential for the development of dorsal mesenchymal protrusion and atrioventricular separation. Lineage tree for the venous pole of the heart: clonal analysis elucidates controversial genealogy based on genetic tracing.
A more detailed understanding of the Nodal signaling pathway and its targets in the heart is required to more fully understand the etiology of congenital heart defects associated with the Nodal signaling pathway.
Requirement for Nodal in Development
Congenital Heart Defects Associated with Perturbations in Nodal Signaling
For example, deletion of an intronic enhancer of Nodal resulted in decreased expression of Nodal in the lateral plate mesoderm. Consistent with Nodal function in left-right patterning, Nodal-dependent target genes are also critical for left-right patterning and heart development [ 21 ]. Pitx2 is perhaps the best described target gene for Nodal signaling and is expressed asymmetrically to the left. side after gastrulation [46]. In mice, germline loss of function of Pitx2 results in left-right asymmetry defects in specific organs, such as the lung [47].
Together, these observations suggest that other unappreciated Nodal-dependent target genes are involved in the establishment of left-right identity and cardiac development. A more complete understanding of the role of Nodal signaling in cardiac development and in congenital heart defects requires a more detailed elucidation of this fundamental pathway, including target genes in the cardiac mesoderm. 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.
A primary requirement for nodes in the formation and maintenance of the primitive streak in the mouse. Cripto is required for proper orientation of the anterior-posterior axis in the mouse embryo. The transcription factor FoxH1 (FAST) mediates node signaling during anterior-posterior patterning and node formation in the mouse.
Broad mesodermal and endodermal deletion of Nodal at postgastrulation stages results in exclusively left/right axial defects. Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Malformations of the left-right axis associated with mutations in ACVR2B, the human type IIB activin receptor gene.
A Foxh1-dependent autoregulatory enhancer controls the level of nodal signals in the mouse embryo. A loss-of-function mutation in the CFC domain of TDGF1 is associated with human forebrain defects. A type IIB activin receptor-mediated signaling pathway controls axial patterning and lateral asymmetry in mice.
G. Knight and Deborah Yelon
- Introduction
- Late-Differentiating Cardiomyocytes Originate from the SHF in Zebrafish
- Mechanisms Regulating Outflow Tract Development in Zebrafish
- Mechanisms Regulating Inflow Tract Development in Zebrafish
- Future Directions and Clinical Implications
- Introduction
- The 22q11.2 Deletion Syndrome (Takao Syndrome)
- Identification of TBX1
- Expression of TBX1
- Mutations of GATA6
- Future Direction: Elucidating the Interaction Between CNC and SHF
Two types of tests have shown that late-differentiating cardiomyocytes are recruited to the poles of the zebrafish heart tube. GFP); Tg(myl7:DsRed) embryos showed that newly differentiated cardiomyocytes populate the cardiac poles 48 hours after fertilization (hpf), while cardiomyocytes in the center of the heart differentiate at an earlier stage (Fig. 25.1a; [5]) . In the early gastrula, the progenitor cells of the outflow tract are located in a medial cranial portion of the ALPM [7].
Studies of the regulation of outflow tract formation have shown conservation of the transcription factors used in zebrafish and mice. Future experiments will be valuable to elucidate the zebrafish equivalent of the mammalian posterior SHF. Overall, the studies summarized here support the value of the zebrafish for investigating SHF development.
In the long term, the use of the zebrafish to analyze the development of SHF will likely shed light on pathways that facilitate our understanding of the etiology of congenital heart disease. Subsequent investigations of the expression pattern of Tbx1 revealed that Tbx1 was surprisingly not detectable in CNC but was expressed in SHF, providing a new concept of the molecular and cellular basis for OFT defects associated with 22q11/Takao syndrome. Progenitor cells derived from the cardiac neural crest (CNC) and second heart field (SHF) play a key role in OFT development.
Interestingly, in mouse and chick embryos Tbx1 is preferentially expressed in the pharyngeal arches, in the ventral half of the otic vesicle and in the head (Fig. Contribution of CNC is considered essential for proper rotation and septation of the OFT. Mutations in GATA6 disrupted its transcriptional activity on downstream target genes involved in the development of the OFT.
Regarding OFT development, clear roles of CNC- and SHF-derived cells have been established [35]. Retinoid signaling is essential for endoderm patterning of the third and fourth pharyngeal arches. Essential roles of the winged helix transcription factor MFH-1 in aortic arch patterning and skeletogenesis.
To solve the problem of the development of these defects, we are interested in the role of the second heart field (SHF) that creates the structure of the outflow tract. Our previous experiments suggested that the sonic hedgehog signal was necessary for the maintenance of Tbx1 expression in the pharyngeal mesoderm including the SHF [1].
![Fig. 25.1 Late-differentiating cardiomyocytes originate from the zebrafish SHF. (a) A develop- develop-mental timing assay reveals late-differentiating cardiomyocytes displaying GFP, but not DsRed [5]](https://thumb-ap.123doks.com/thumbv2/1libvncom/10205126.0/21.659.117.542.93.703/differentiating-cardiomyocytes-originate-zebrafish-develop-differentiating-cardiomyocytes-displaying.webp)
OFT Ao
Tbx1 hypomorphic allele (Tbx1neo/þ) [2] for attempting to recapitulate human genotype and phenotype correlation. Mice homozygous for this hypomorphic allele expressed about 25% of Tbx1 mRNA compared to wild-type mice. We demonstrated that Tbx1 is a dosage-dependent gene and believe that Tbx1 dosage may be affected by genetic and/or environmental modifiers due to the highly variable phenotype of 22q11DS rather than the relatively uniform chromosomal microdeletion.
We try to recreate the phenotype variability of PTA in this hypomorphic model (Fig. 28.1) by application of environmental modifiers. 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.
Ao OFT septum
Tbx1 regulates fibroblast growth factors in the anterior cardiac field through a reinforcing autoregulatory loop involving forkhead transcription factors.
Vascular Development and Diseases
Introduction
Tissues, including the cardiovascular system, are composed of various cells and the extracellular matrix (ECM) synthesized by these cells. Higher-order structures consisting of cells and fibrous elements are formed during development and remodeled during tissue repair/regeneration after injury. In addition to their physical role, several ECM molecules provide important biological signaling that affects various cellular functions in physiological and pathological tissue remodeling.
Tenascin-C (TNC) is a prototype matricellular protein expressed during embryonic development and tissue repair after injury. This chapter will focus on the role of TNC in vascular development, particularly in the coronary arteries and aorta.
Extracellular Matrix in Vascular Wall
