scholarly journals Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption

Development ◽  
2001 ◽  
Vol 128 (16) ◽  
pp. 3061-3070 ◽  
Author(s):  
Leonard Feiner ◽  
Andrea L. Webber ◽  
Christopher B. Brown ◽  
Min Min Lu ◽  
Li Jia ◽  
...  
Keyword(s):  
Neural Crest ◽  
Aortic Arch ◽  
Heart Defects ◽  
Outflow Tract ◽  
Targeted Mutagenesis ◽  
Mutant Mice ◽  
Persistent Truncus Arteriosus ◽  
Cardiovascular Defects ◽  
Cardiac Outflow

Semaphorin 3C is a secreted member of the semaphorin gene family. To investigate its function in vivo, we have disrupted the semaphorin 3Clocus in mice by targeted mutagenesis. semaphorin 3C mutant mice die within hours after birth from congenital cardiovascular defects consisting of interruption of the aortic arch and improper septation of the cardiac outflow tract. This phenotype is similar to that reported following ablation of the cardiac neural crest in chick embryos and resembles congenital heart defects seen in humans. Semaphorin 3C is expressed in the cardiac outflow tract as neural crest cells migrate into it. Their entry is disrupted in semaphorin 3C mutant mice. These data suggest that semaphorin 3C promotes crest cell migration into the proximal cardiac outflow tract.

Abstract 939: Galpha-i Signaling in Neural Crest Cells is Required for Normal Migration of Cardiac Neural Crest Cells, Cardiac Development, and Survival

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Kathleen M Ruppel ◽  
Hiroshi Kataoka ◽  
Michelle Iwaki ◽  
Ivo Cornelissen ◽  
Shaun R Coughlin
Keyword(s):  
Neural Crest ◽  
Signaling Pathways ◽  
Aortic Arch ◽  
G Protein ◽  
Heart Defects ◽  
Neural Crest Cells ◽  
Outflow Tract ◽  
Potential Candidate ◽  
Dependent Manner ◽  
Cardiovascular Development

G protein coupled receptors (GPCRs) have long been known to play crucial roles in transducing environmental signals to the adult cardiovascular system. In recent years, the roles of G protein-mediated signaling pathways in orchestrating the interactions of different tissues during cardiovascular development have become increasingly evident. To analyze the role of G protein signaling pathways in vivo we have generated mice where the function of the heterotrimeric G alpha subunit Gai can be ablated in a cell type specific manner utilizing the Cre-loxP system. We have mated these mice to two different neural crest-specific Cre lines in order to probe the effects of loss of Gai mediated signaling on the ability of neural crest cells (NCC) to contribute to the developing outflow tract and aortic arch arteries. METHODS: We have generated mice that express the Gai-inhibiting pertussis toxin S1 subunit (PTX) from the ROSA26 locus in a Cre recombination dependent manner (ROSA-PTX mice). These were mated to mice expressing either the Wnt1 Cre or P0 Cre transgene. Wnt1Cre is active in both premigratory and migratory NCC, whereas P0Cre is active only in migratory NCC and their derivatives. RESULTS: P0Cre-ROSA-PTX mice were normal at birth and demonstrated no structural heart defects. In contrast, Wnt1Cre-ROSA-PTX mice were present in normal numbers at late gestation but died perinatally due in part to cardiac outflow tract defects. Excision reporter and in situ hybridization studies suggest this is secondary to a delay/blockage of cardiac NCC migration into the developing outflow tract. NCC migration into the pharyngeal arches was unaffected in these mice and no craniofacial, thymic, or aortic arch abnormalities were observed. CONCLUSIONS: These results indicate that Gai-mediated signaling is required in premigratory or early migratory cardiac NCC for normal development of the outflow tract. In contrast, endothelin A receptor knockout mice (currently the only GPCR knock out with a neural crest phenotype) are thought to exhibit defects of postmigratory NCC function. RNA profiling of NCC for GPCRs involved in this Gai-dependent pathway has revealed several potential candidate receptors, including orphan receptors. Further analysis of these receptors is underway.

Pax3 is required for cardiac neural crest migration in the mouse: evidence from the splotch (Sp2H) mutant

Development ◽  
1997 ◽  
Vol 124 (2) ◽  
pp. 505-514 ◽  
Author(s):  
S.J. Conway ◽  
D.J. Henderson ◽  
A.J. Copp
Keyword(s):  
Neural Crest ◽  
Neural Tube ◽  
Neural Crest Cells ◽  
Outflow Tract ◽  
Avian Embryo ◽  
Cardiac Neural Crest ◽  
Branchial Arches ◽  
Aortic Arches ◽  
Cardiac Outflow

Neural crest cells originating in the occipital region of the avian embryo are known to play a vital role in formation of the septum of the cardiac outflow tract and to contribute cells to the aortic arches, thymus, thyroid and parathyroids. This ‘cardiac’ neural crest sub-population is assumed to exist in mammals, but without direct evidence. In this paper we demonstrate, using RT-PCR and in situ hybridisation, that Pax3 expression can serve as a marker of cardiac neural crest cells in the mouse embryo. Cells of this lineage were traced from the occipital neural tube, via branchial arches 3, 4 and 6, into the aortic sac and aorto-pulmonary outflow tract. Confirmation that these Pax3-positive cells are indeed cardiac neural crest is provided by experiments in which hearts were deprived of a source of colonising neural crest, by organ culture in vitro, with consequent lack of up-regulation of Pax3. Occipital neural crest cell outgrowths in vitro were also shown to express Pax3. Mutation of Pax3, as occurs in the splotch (Sp2H) mouse, results in development of conotruncal heart defects including persistent truncus arteriosus. Homozygotes also exhibit defects of the aortic arches, thymus, thyroid and parathyroids. Pax3-positive neural crest cells were found to emigrate from the occipital neural tube of Sp2H/Sp2H embryos in a relatively normal fashion, but there was a marked deficiency or absence of neural crest cells traversing branchial arches 3, 4 and 6, and entering the cardiac outflow tract. This decreased expression of Pax3 in Sp2H/Sp2H embryos was not due to down-regulation of Pax3 in neural crest cells, as use of independent neural crest markers, Hoxa-3, CrabpI, Prx1, Prx2 and c-met also revealed a deficiency of migrating cardiac neural crest cells in homozygous embryos. This work demonstrates the essential role of the cardiac neural crest in formation of the heart and great vessels in the mouse and, furthermore, shows that Pax3 function is required for the cardiac neural crest to complete its migration to the developing heart.

scholarly journals Gap Junction–mediated Cell–Cell Communication Modulates Mouse Neural Crest Migration

1998 ◽  
Vol 143 (6) ◽  
pp. 1725-1734 ◽  
Author(s):  
G.Y. Huang ◽  
E.S. Cooper ◽  
K. Waldo ◽  
M.L. Kirby ◽  
N.B. Gilula ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Neural Crest ◽  
Gap Junction ◽  
Heart Defects ◽  
Neural Crest Cells ◽  
Dominant Negative ◽  
Cardiac Neural Crest ◽  
Gap Junction Communication ◽  
Neural Crest Migration

Previous studies showed that conotruncal heart malformations can arise with the increase or decrease in α1 connexin function in neural crest cells. To elucidate the possible basis for the quantitative requirement for α1 connexin gap junctions in cardiac development, a neural crest outgrowth culture system was used to examine migration of neural crest cells derived from CMV43 transgenic embryos overexpressing α1 connexins, and from α1 connexin knockout (KO) mice and FC transgenic mice expressing a dominant-negative α1 connexin fusion protein. These studies showed that the migration rate of cardiac neural crest was increased in the CMV43 embryos, but decreased in the FC transgenic and α1 connexin KO embryos. Migration changes occurred in step with connexin gene or transgene dosage in the homozygous vs. hemizygous α1 connexin KO and CMV43 embryos, respectively. Dye coupling analysis in neural crest cells in the outgrowth cultures and also in the living embryos showed an elevation of gap junction communication in the CMV43 transgenic mice, while a reduction was observed in the FC transgenic and α1 connexin KO mice. Further analysis using oleamide to downregulate gap junction communication in nontransgenic outgrowth cultures showed that this independent method of reducing gap junction communication in cardiac crest cells also resulted in a reduction in the rate of crest migration. To determine the possible relevance of these findings to neural crest migration in vivo, a lacZ transgene was used to visualize the distribution of cardiac neural crest cells in the outflow tract. These studies showed more lacZ-positive cells in the outflow septum in the CMV43 transgenic mice, while a reduction was observed in the α1 connexin KO mice. Surprisingly, this was accompanied by cell proliferation changes, not in the cardiac neural crest cells, but in the myocardium— an elevation in the CMV43 mice vs. a reduction in the α1 connexin KO mice. The latter observation suggests that cardiac neural crest cells may have a role in modulating growth and development of non–neural crest– derived tissues. Overall, these findings suggest that gap junction communication mediated by α1 connexins plays an important role in cardiac neural crest migration. Furthermore, they indicate that cardiac neural crest perturbation is the likely underlying cause for heart defects in mice with the gain or loss of α1 connexin function.

scholarly journals Sonic hedgehog is required for cardiac outflow tract and neural crest cell development

2005 ◽  
Vol 283 (2) ◽  
pp. 357-372 ◽  
Author(s):  
I. Washington Smoak ◽  
N.A. Byrd ◽  
R. Abu-Issa ◽  
M.M. Goddeeris ◽  
R. Anderson ◽  
...  
Keyword(s):  
Neural Crest ◽  
Sonic Hedgehog ◽  
Neural Crest Cell ◽  
Cell Development ◽  
Outflow Tract ◽  
Crest Cell ◽  
Cardiac Outflow

scholarly journals Cardiac neural crest ablation results in early endocardial cushion and hemodynamic flow abnormalities

2016 ◽  
Vol 311 (5) ◽  
pp. H1150-H1159 ◽  
Author(s):  
Pei Ma ◽  
Shi Gu ◽  
Ganga H. Karunamuni ◽  
Michael W. Jenkins ◽  
Michiko Watanabe ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Neural Crest ◽  
Late Stage ◽  
Heart Defects ◽  
Neural Crest Cell ◽  
Vessel Diameter ◽  
Double Outlet Right Ventricle ◽  
Great Vessel ◽  
Persistent Truncus Arteriosus ◽  
Cardiac Neural Crest

Cardiac neural crest cell (CNCC) ablation creates congenital heart defects (CHDs) that resemble those observed in many syndromes with craniofacial and cardiac consequences. The loss of CNCCs causes a variety of great vessel defects, including persistent truncus arteriosus and double-outlet right ventricle. However, because of the lack of quantitative volumetric measurements, less severe defects, such as great vessel size changes and valve defects, have not been assessed. Also poorly understood is the role of abnormal cardiac function in the progression of CNCC-related CHDs. CNCC ablation was previously reported to cause abnormal cardiac function in early cardiogenesis, before the CNCCs arrive in the outflow region of the heart. However, the affected functional parameters and how they correlate with the structural abnormalities were not fully characterized. In this study, using a CNCC-ablated quail model, we contribute quantitative phenotyping of CNCC ablation-related CHDs and investigate abnormal early cardiac function, which potentially contributes to late-stage CHDs. Optical coherence tomography was used to assay early- and late-stage embryos and hearts. In CNCC-ablated embryos at four-chambered heart stages, great vessel diameter and left atrioventricular valve leaflet volumes are reduced. Earlier, at cardiac looping stages, CNCC-ablated embryos exhibit abnormally twisted bodies, abnormal blood flow waveforms, increased retrograde flow percentage, and abnormal cardiac cushions. The phenotypes observed in this CNCC-ablation model were also strikingly similar to those found in an established avian fetal alcohol syndrome model, supporting the contribution of CNCC dysfunction to the development of alcohol-induced CHDs.

Essential roles of the winged helix transcription factor MFH-1 in aortic arch patterning and skeletogenesis

Development ◽  
1997 ◽  
Vol 124 (22) ◽  
pp. 4627-4638 ◽  
Author(s):  
K. Iida ◽  
H. Koseki ◽  
H. Kakinuma ◽  
N. Kato ◽  
Y. Mizutani-Koseki ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Neural Crest ◽  
Aortic Arch ◽  
Interrupted Aortic Arch ◽  
Targeted Mutagenesis ◽  
Winged Helix ◽  
Cartilaginous Tissues ◽  
Early Embryos ◽  
Skeletal Defects ◽  
Winged Helix Transcription Factor

Mesenchyme Fork Head-1 (MFH-1) is a forkhead (also called winged helix) transcription factor defined by a common 100-amino acid DNA-binding domain. MFH-1 is expressed in non-notochordal mesoderm in the prospective trunk region and in cephalic neural-crest and cephalic mesoderm-derived mesenchymal cells in the prechordal region of early embryos. Subsequently, strong expression is localized in developing cartilaginous tissues, kidney and dorsal aortas. To investigate the developmental roles of MFH-1 during embryogenesis, mice lacking the MFH-1 locus were generated by targeted mutagenesis. MFH-1-deficient mice died embryonically and perinatally, and exhibited interrupted aortic arch and skeletal defects in the neurocranium and the vertebral column. Interruption of the aortic arch seen in the mutant mice was the same as in human congenital anomalies. These results suggest that MFH-1 has indispensable roles during the extensive remodeling of the aortic arch in neural-crest-derived cells and in skeletogenesis in cells derived from the neural crest and the mesoderm.

scholarly journals Cardiac outflow tract septation failure in Pax3-deficient embryos is due to p53-dependent regulation of migrating cardiac neural crest

2008 ◽  
Vol 125 (9-10) ◽  
pp. 757-767 ◽  
Author(s):  
Sarah C. Morgan ◽  
Hyung-Yul Lee ◽  
Frédéric Relaix ◽  
Lisa L. Sandell ◽  
John M. Levorse ◽  
...  
Keyword(s):  
Neural Crest ◽  
Outflow Tract ◽  
Cardiac Neural Crest ◽  
Cardiac Outflow
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