A genetic link between Tbx1 and fibroblast growth factor signaling

Development ◽  
2002 ◽  
Vol 129 (19) ◽  
pp. 4605-4611 ◽  
Author(s):  
Francesca Vitelli ◽  
Ilaria Taddei ◽  
Masae Morishima ◽  
Erik N. Meyers ◽  
Elizabeth A. Lindsay ◽  
...  
Keyword(s):  
Aortic Arch ◽  
Expression Patterns ◽  
Pharyngeal Arch ◽  
Growth Factor Signaling ◽  
Expression Domain ◽  
Primary Defect ◽  
Genetic Link ◽  
Pharyngeal Endoderm ◽  
Pharyngeal Arch Arteries ◽  
Tbx1 Haploinsufficiency

Tbx1 haploinsufficiency causes aortic arch abnormalities in mice because of early growth and remodeling defects of the fourth pharyngeal arch arteries. The function of Tbx1 in the development of these arteries is probably cell non-autonomous, as the gene is not expressed in structural components of the artery but in the surrounding pharyngeal endoderm. We hypothesized that Tbx1 may trigger signals from the pharyngeal endoderm directed to the underlying mesenchyme. We show that the expression patterns of Fgf8 and Fgf10, which partially overlap with Tbx1 expression pattern, are altered in Tbx1–/– mutants. In particular, Fgf8 expression is abolished in the pharyngeal endoderm. To understand the significance of this finding for the pathogenesis of the mutant Tbx1 phenotype, we crossed Tbx1 and Fgf8 mutants. Double heterozygous Tbx1+/–;Fgf8+/– mutants present with a significantly higher penetrance of aortic arch artery defects than do Tbx1+/–;Fgf8+/+ mutants, while Tbx1+/+;Fgf8+/– animals are normal. We found that Fgf8 mutation increases the severity of the primary defect caused by Tbx1 haploinsufficiency, i.e. early hypoplasia of the fourth pharyngeal arch arteries, consistent with the time and location of the shared expression domain of the two genes. Hence, Tbx1 and Fgf8 interact genetically in the development of the aortic arch. Our data provide the first evidence of a genetic link between Tbx1 and FGF signaling, and the first example of a modifier of the Tbx1 haploinsufficiency phenotype. We speculate that the FGF8 locus might affect the penetrance of cardiovascular defects in individuals with chromosome 22q11 deletions involving TBX1.

scholarly journals Cell - ECM Interactions Play Multiple Essential Roles in Aortic Arch Development

2020 ◽  
Author(s):  
Michael Warkala ◽  
Dongying Chen ◽  
AnnJosette Ramirez ◽  
Ali Jubran ◽  
Michael J Schonning ◽  
...  
Keyword(s):  
Aortic Arch ◽  
Developmental Stages ◽  
Lineage Tracing ◽  
Confocal Imaging ◽  
Pharyngeal Arch ◽  
Cellular Mechanisms ◽  
Integrin Α5β1 ◽  
Pharyngeal Arches ◽  
Heart Field ◽  
Pharyngeal Arch Arteries

Rationale: Defects in the morphogenesis of the 4th pharyngeal arch arteries (PAAs) give rise to lethal birth defects. Understanding genes and mechanisms regulating PAA formation will provide important insights into the etiology and treatments for congenital heart disease. Objective: Cell-ECM interactions play essential roles in the morphogenesis of PAAs and their derivatives, the aortic arch artery (AAA) and its major branches; however, their specific functions are not well-understood. Previously, we demonstrated that integrin α5β1 and fibronectin (Fn1) expressed in the Isl1 lineages regulate PAA formation. The objective of the current studies was to investigate cellular mechanisms by which integrin α5β1 and Fn1 regulate AAA morphogenesis. Methods and Results: Using temporal lineage tracing, whole-mount confocal imaging, and quantitative analysis of the second heart field (SHF) and endothelial cell (EC) dynamics, we show that the majority of PAA EC progenitors arise by E7.5 in the SHF and contribute to pharyngeal arch endothelium between E7.5 and E9.5. Consequently, SHF-derived ECs in the pharyngeal arches form a uniform plexus of small blood vessels, which remodels into the PAAs by 35 somites. The remodeling of the vascular plexus is orchestrated by signals dependent on the pharyngeal ECM microenvironment, extrinsic to the endothelium. Conditional ablation of integrin α5β1 or Fn1 in the Isl1 lineages showed that signaling by the ECM regulates AAA morphogenesis at multiple steps: 1) accumulation of SHF-derived ECs in the pharyngeal arches, 2) remodeling of the uniform EC plexus in the 4th arches into the PAAs; and 3) differentiation of neural crest-derived cells adjacent to the PAA endothelium into vascular smooth muscle cells. Conclusions: PAA formation is a multi-step process entailing dynamic contribution of SHF-derived ECs to pharyngeal arches, the remodeling of endothelial plexus into the PAAs, and the remodeling of the PAAs into the AAA and its major branches. Cell-ECM interactions regulated by integrin α5β1 and Fn1 play essential roles at each of these developmental stages.

scholarly journals Cell – ECM interactions play distinct and essential roles at multiple stages during the development of the aortic arch

2020 ◽  
Author(s):  
Michael Warkala ◽  
Dongying Chen ◽  
Ali Jubran ◽  
AnnJosette Ramirez ◽  
Michael Schonning ◽  
...  
Keyword(s):  
Aortic Arch ◽  
Developmental Stages ◽  
Lineage Tracing ◽  
Confocal Imaging ◽  
Pharyngeal Arch ◽  
Cellular Mechanisms ◽  
Integrin Α5β1 ◽  
Pharyngeal Arches ◽  
Heart Field ◽  
Pharyngeal Arch Arteries

RationaleDefects in the morphogenesis of the 4th pharyngeal arch arteries (PAAs) give rise to lethal birth defects. Understanding genes and mechanisms regulating PAA formation will provide important insights into the etiology and treatments for congenital heart disease.ObjectiveCell-ECM interactions play essential roles in the morphogenesis of PAAs and their derivatives, the aortic arch artery (AAA) and its major branches; however, their specific functions are not well-understood. Previously, we demonstrated that integrin α5β1 and fibronectin (Fn1) expressed in the Isl1 lineages regulate PAA formation. The objective of these studies was to investigate cellular mechanisms by which integrin α5β1 and Fn1 regulate AAA morphogenesis.Methods and ResultsUsing temporal lineage tracing, whole-mount confocal imaging, and quantitative analysis of the second heart field (SHF) and endothelial cell (EC) dynamics, we show that the majority of PAA EC progenitors arise by E7.5 in the SHF and populate pharyngeal arch mesenchyme between E7.5 and E9.5. Consequently, SHF-derived ECs in the pharyngeal arches become organized into a uniform plexus of small blood vessels, which becomes remodeled into the PAAs between 31 – 35 somites. The remodeling of the vascular plexus is orchestrated by signals dependent on pharyngeal ECM microenvironment extrinsic to the endothelium. Conditional ablation of integrin α5β1 or Fn1 in the Isl1 lineages showed that signaling by the ECM regulates AAA morphogenesis at multiple steps: 1) the recruitment of the SHF-derived ECs into the pharyngeal arches, 2) the remodeling of the uniform EC plexus in the 4th arches into the PAAs; and 3) differentiation of neural crest-derived cells abutting the PAA endothelium into vascular smooth muscle cells.ConclusionsPAA formation is a multi-step process entailing dynamic contribution of SHF-derived ECs to pharyngeal arches, the remodeling of endothelial plexus into the PAAs, and the remodeling of the PAAs into the AAA and its major branches. Cell-ECM interactions regulated by integrin α5β1 and Fn1 play essential roles at each of these developmental stages.

How best to describe the pharyngeal arch arteries when the fifth arch does not exist?

2020 ◽  
Vol 30 (11) ◽  
pp. 1708-1710
Author(s):  
Robert H. Anderson ◽  
Simon D. Bamforth ◽  
Saurabh Kumar Gupta
Keyword(s):  
Aortic Arch ◽  
Human Fetus ◽  
Right Aortic Arch ◽  
Developmental Changes ◽  
Pharyngeal Arch ◽  
Pharyngeal Arches ◽  
Pharyngeal Arch Arteries ◽  
Collateral Channel

AbstractIn the accompanying article appearing in this issue of the Journal, Prabhu and his colleagues, from Bengalaru in India, describe their experience with patients having a right aortic arch. They discuss the fact that the anomalous arrangements they encountered can all be interpreted on the basis of the hypothetical double arch proposed by Edwards. They point to the fact that interpretation of the developmental changes underscoring the production of the double arch is currently confused by reference to the so-called Rathke diagram, in which six sets of arteries are shown extending through the mesenchyme of the pharyngeal arches. As the authors point out, Graham and his associates have now shown that the alleged fifth set of pharyngeal arches do not exist. Based on our own observations, we endorse this statement. It means that new explanations must now be provided for the lesions previously described on the basis of persistence of the alleged artery of the fifth pharyngeal arch. We have previously claimed to have observed such an artery in a human fetus. We now believe, on the basis of our latest findings, that our earlier observation is better explained on the basis of presence of a collateral channel. We suggest that the so-called “fifth arch arteries” are themselves then best explained either on the basis of existence of such collateral channels, or remodelling of the aortic sac, which is the manifold, during development, that gives rise to the pharyngeal arch arteries.

Expression of AmphiHox-1 and AmphiPax-1 in amphioxus embryos treated with retinoic acid: insights into evolution and patterning of the chordate nerve cord and pharynx

Development ◽  
1996 ◽  
Vol 122 (6) ◽  
pp. 1829-1838 ◽  
Author(s):  
L.Z. Holland ◽  
N.D. Holland
Keyword(s):  
Retinoic Acid ◽  
Neural Crest ◽  
Nerve Cord ◽  
Hox Genes ◽  
Expression Patterns ◽  
Expression Domain ◽  
Craniofacial Malformations ◽  
Pharyngeal Arches ◽  
Pharyngeal Endoderm ◽  
Cerebral Vesicle

Excess all-trans retinoic acid (RA) causes severe craniofacial malformations in vertebrate embryos: pharyngeal arches are fused or absent, and a rostrad expansion of Hoxb-1 expression in the hindbrain shows that anterior rhombomeres are homeotically respecified to a more posterior identity. As a corollary, neural crest migration into the pharyngeal arches is abnormal. We administered excess RA to developing amphioxus, the closest invertebrate relative of the vertebrates and thus a key organism for understanding evolution of the vertebrate body plan. In normal amphioxus, the nerve cord has only a slight anterior swelling, the cerebral vesicle, and apparently lacks migratory neural crest. Nevertheless, excess RA similarly affects amphioxus and vertebrates. The expression domain of AmphiHox-1 (homologous to mouse Hoxb-1) in the amphioxus nerve cord is also extended anteriorly. For both the amphioxus and mouse genes, excess RA causes either (1) continuous expression throughout the preotic hindbrain (mouse) and from the level of somite 7 to the anterior end of the nerve cord (amphioxus) or (2) discontinuous expression with a gap in rhombomere 3 (mouse) and a gap at the posterior end of the cerebral vesicle (amphioxus). A comparison of these expression patterns suggests that amphioxus has a homolog of the vertebrate hindbrain, both preotic and postotic. Although RA alters the expression of AmphiHox-1 expression in the amphioxus nerve cord, it does not alter the expression of AmphiHox-1 in presomitic mesoderm or of alkali myosin light chain (AmphiMlc-alk) in somites, and the axial musculature and notochord develop normally. The most striking morphogenetic effect of RA on amphioxus larvae is the failure of mouth and gill slits to form. In vertebrates effects of excess RA on pharyngeal development have been attributed solely to the abnormal migratory patterns of Hox-expressing cranial neural crest cells. This cannot be true for amphioxus because of the lack of migratory neural crest. Furthermore, expression of Hox genes in pharyngeal tissues of amphioxus has not yet been detected. However, the absence of gill slits in RA-treated amphioxus embryos correlates with an RA-induced failure of AmphiPax-1 to become down-regulated in regions of pharyngeal endoderm that would normally fuse with the overlying ectoderm. In vertebrates, RA might similarly act via Pax-1/9, also expressed in pharyngeal endoderm, to impair pharyngeal patterning.

scholarly journals Msx1 haploinsufficiency modifies the Pax9-deficient cardiovascular phenotype

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ramada R. Khasawneh ◽  
Ralf Kist ◽  
Rachel Queen ◽  
Rafiqul Hussain ◽  
Jonathan Coxhead ◽  
...  
Keyword(s):  
Neural Crest ◽  
Aortic Arch ◽  
Thyroid Cartilage ◽  
Neural Crest Cell ◽  
Pharyngeal Arch ◽  
Palate Development ◽  
The Third ◽  
Pharyngeal Endoderm ◽  
Cardiovascular Defects ◽  
Crest Cell

Abstract Background Successful embryogenesis relies on the coordinated interaction between genes and tissues. The transcription factors Pax9 and Msx1 genetically interact during mouse craniofacial morphogenesis, and mice deficient for either gene display abnormal tooth and palate development. Pax9 is expressed specifically in the pharyngeal endoderm at mid-embryogenesis, and mice deficient for Pax9 on a C57Bl/6 genetic background also have cardiovascular defects affecting the outflow tract and aortic arch arteries giving double-outlet right ventricle, absent common carotid arteries and interruption of the aortic arch. Results In this study we have investigated both the effect of a different genetic background and Msx1 haploinsufficiency on the presentation of the Pax9-deficient cardiovascular phenotype. Compared to mice on a C57Bl/6 background, congenic CD1-Pax9–/– mice displayed a significantly reduced incidence of outflow tract defects but aortic arch defects were unchanged. Pax9–/– mice with Msx1 haploinsufficiency, however, have a reduced incidence of interrupted aortic arch, but more cases with cervical origins of the right subclavian artery and aortic arch, than seen in Pax9–/– mice. This alteration in arch artery defects was accompanied by a rescue in third pharyngeal arch neural crest cell migration and smooth muscle cell coverage of the third pharyngeal arch arteries. Although this change in phenotype could theoretically be compatible with post-natal survival, using tissue-specific inactivation of Pax9 to maintain correct palate development whilst inducing the cardiovascular defects was unable to prevent postnatal death in the mutant mice. Hyoid bone and thyroid cartilage formation were abnormal in Pax9–/– mice. Conclusions Msx1 haploinsufficiency mitigates the arch artery defects in Pax9–/– mice, potentially by maintaining the survival of the 3rd arch artery through unimpaired migration of neural crest cells to the third pharyngeal arches. With the neural crest cell derived hyoid bone and thyroid cartilage also being defective in Pax9–/– mice, we speculate that the pharyngeal endoderm is a key signalling centre that impacts on neural crest cell behaviour highlighting the ability of cells in different tissues to act synergistically or antagonistically during embryo development.

scholarly journals Pax9 is required for cardiovascular development and interacts with Tbx1 in the pharyngeal endoderm to control 4th pharyngeal arch artery morphogenesis

2019 ◽  
Author(s):  
Helen M. Phillips ◽  
Catherine A. Stothard ◽  
Wasay Mohiuddin Shaikh Qureshi ◽  
Anastasia I. Kousa ◽  
J. Alberto Briones-Leon ◽  
...  
Keyword(s):  
Aortic Arch ◽  
Genetic Interaction ◽  
Interrupted Aortic Arch ◽  
Outflow Tract ◽  
Pharyngeal Arch ◽  
Cardiovascular Development ◽  
Developmental Defects ◽  
Pharyngeal Endoderm ◽  
Pharyngeal Arch Artery ◽  
Aortic Arch Arteries

AbstractDevelopmental defects affecting the heart and aortic arch arteries are a key phenotype observed in DiGeorge syndrome patients and are caused by a microdeletion on chromosome 22q11. Heterozygosity of TBX1, one of the deleted genes, is expressed throughout the pharyngeal arches and is considered a key component for the arch artery defects. Pax9 is expressed in the pharyngeal endoderm and is downregulated in Tbx1 mutant mice. We show here that Pax9 deficient mice are born with complex cardiovascular malformations affecting the outflow tract and aortic arch arteries with failure of the 3rd and 4th pharyngeal arch arteries to form correctly. Transcriptome analysis indicated that Pax9 and Tbx1 may function together, and mice double heterozygous for Tbx1/Pax9 presented with a significantly increased incidence of interrupted aortic arch when compared to Tbx1 heterozygous mice. Using a novel Pax9Cre allele we demonstrated that the site of this Tbx1-Pax9 genetic interaction is in the pharyngeal endoderm, therefore revealing that a Tbx1/Pax9-controlled signalling mechanism emanating from the pharyngeal endoderm is required for critical tissue interactions during normal morphogenesis of the pharyngeal arch artery system.Summary statementPax9 is required for outflow tract and aortic arch development, and functions together with Tbx1 in the pharyngeal endoderm for 4th arch artery formation.

scholarly journals Msx1 Haploinsufficiency Modifies the Pax9-Deficient Cardiovascular Phenotype

2021 ◽  
Author(s):  
Ramada R. Khasawneh ◽  
Ralf Kist ◽  
Jürgen E Schneider ◽  
Timothy J Mohun ◽  
Heiko Peters ◽  
...  
Keyword(s):  
Neural Crest ◽  
Aortic Arch ◽  
Thyroid Cartilage ◽  
Neural Crest Cell ◽  
Pharyngeal Arch ◽  
Palate Development ◽  
The Third ◽  
Pharyngeal Endoderm ◽  
Cardiovascular Defects ◽  
Crest Cell

Abstract Background Successful embryogenesis relies on the coordinated interaction between genes and tissues. The transcription factors Pax9 and Msx1 genetically interact during mouse craniofacial morphogenesis, and mice deficient for either gene display abnormal tooth and palate development. Pax9 is expressed specifically in the pharyngeal endoderm at mid-embryogenesis, and mice deficient for Pax9 on a C57Bl/6 genetic background also have cardiovascular defects affecting the outflow tract and aortic arch arteries giving double-outlet right ventricle, absent common carotid arteries and interruption of the aortic arch. Results In this study we have investigated both the effect of a different genetic background and Msx1 haploinsufficiency on the presentation of the Pax9-deficient cardiovascular phenotype. Compared to mice on a C57Bl/6 background, congenic CD1-Pax9−/− mice displayed a significantly reduced incidence of outflow tract defects but aortic arch defects were unchanged. Pax9−/− mice with Msx1 haploinsufficiency, however, have a reduced incidence of interrupted aortic arch, but more cases with cervical origins of the right subclavian artery and aortic arch, than seen in Pax9−/− mice. This alteration in arch artery defects was accompanied by a rescue in third pharyngeal arch neural crest cell migration and smooth muscle cell coverage of the third pharyngeal arch arteries. Although this change in phenotype could theoretically be compatible with post-natal survival, using tissue-specific inactivation of Pax9 to maintain correct palate development whilst inducing the cardiovascular defects was unable to prevent postnatal death in the mutant mice. Hyoid bone and thyroid cartilage formation were abnormal in Pax9−/− mice. Conclusions Msx1 haploinsufficiency mitigates the arch artery defects in Pax9−/− mice, potentially by maintaining the survival of the 3rd arch artery through unimpaired migration of neural crest cells to the third pharyngeal arches. With the neural crest cell derived hyoid bone and thyroid cartilage also being defective in Pax9−/− mice, we speculate that the pharyngeal endoderm is a key signalling centre that impacts on neural crest cell behaviour highlighting the ability of cells in different tissues to act synergistically or antagonistically during embryo development.

scholarly journals Foxc2 in pharyngeal arch mesenchyme is important for aortic arch artery remodelling and ventricular septum formation

2015 ◽  
Vol 36 (4) ◽  
pp. 235-245 ◽  
Author(s):  
Mohammad Khaja Mafij UDDIN ◽  
Wataru KIMURA ◽  
Tomoyuki ISHIKURA ◽  
Haruhiko KOSEKI ◽  
Nobuaki YOSHIDA ◽  
...  
Keyword(s):  
Aortic Arch ◽  
Ventricular Septum ◽  
Pharyngeal Arch
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