Abstract 575: Primary Cilia of Cardiac Neural Crest Cells Orchestrate Multiple Aspects of Cardiovascular Development

Although it is well established that transgenic manipulation of mammalian neural crest-related gene expression and microsurgical removal of premigratory chicken andXenopusembryonic cardiac neural crest progenitors results in a wide spectrum of both structural and functional congenital heart defects, the actual functional mechanism of the cardiac neural crest cells within the heart is poorly understood. Neural crest cell migration and appropriate colonization of the pharyngeal arches and outflow tract septum is thought to be highly dependent on genes that regulate cell-autonomous polarized movement (i.e., gap junctions, cadherins, and noncanonicalWnt1pathway regulators). Once the migratory cardiac neural crest subpopulation finally reaches the heart, they have traditionally been thought to participate in septation of the common outflow tract into separate aortic and pulmonary arteries. However, several studies have suggested these colonizing neural crest cells may also play additional unexpected roles during cardiovascular development and may even contribute to a crest-derived stem cell population. Studies in both mice and chick suggest they can also enter the heart from the venous inflow as well as the usual arterial outflow region, and may contribute to the adult semilunar and atrioventricular valves as well as part of the cardiac conduction system. Furthermore, although they are not usually thought to give rise to the cardiomyocyte lineage, neural crest cells in the zebrafish (Danio rerio) can contribute to the myocardium and may have different functions in a species-dependent context. Intriguingly, both ablation of chick andXenopuspremigratory neural crest cells, and a transgenic deletion of mouse neural crest cell migration or disruption of the normal mammalian neural crest gene expression profiles, disrupts ventral myocardial function and/or cardiomyocyte proliferation. Combined, this suggests that either the cardiac neural crest secrete factor/s that regulate myocardial proliferation, can signal to the epicardium to subsequently secrete a growth factor/s, or may even contribute directly to the heart. Although there are species differences between mouse, chick, and Xenopus during cardiac neural crest cell morphogenesis, recent data suggest mouse and chick are more similar to each other than to the zebrafish neural crest cell lineage. Several groups have used the genetically definedPax3(splotch) mutant mice model to address the role of the cardiac neural crest lineage. Here we review the current literature, the neural crest-related role of thePax3transcription factor, and discuss potential function/s of cardiac neural crest-derived cells during cardiovascular developmental remodeling.

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The Cardiac Neural Crest Cells in Heart Development and Congenital Heart Defects

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd8080089 ◽

2021 ◽

Vol 8 (8) ◽

pp. 89

Author(s):

Shannon Erhardt ◽

Mingjie Zheng ◽

Xiaolei Zhao ◽

Tram P. Le ◽

Tina O. Findley ◽

...

Keyword(s):

Neural Crest ◽

Signaling Pathways ◽

Congenital Heart Defects ◽

Heart Development ◽

Congenital Heart ◽

Heart Defects ◽

Interventricular Septum ◽

Neural Crest Cells ◽

Cardiovascular Development ◽

Cardiac Neural Crest

The neural crest (NC) is a multipotent and temporarily migratory cell population stemming from the dorsal neural tube during vertebrate embryogenesis. Cardiac neural crest cells (NCCs), a specified subpopulation of the NC, are vital for normal cardiovascular development, as they significantly contribute to the pharyngeal arch arteries, the developing cardiac outflow tract (OFT), cardiac valves, and interventricular septum. Various signaling pathways are shown to orchestrate the proper migration, compaction, and differentiation of cardiac NCCs during cardiovascular development. Any loss or dysregulation of signaling pathways in cardiac NCCs can lead to abnormal cardiovascular development during embryogenesis, resulting in abnormalities categorized as congenital heart defects (CHDs). This review focuses on the contributions of cardiac NCCs to cardiovascular formation, discusses cardiac defects caused by a disruption of various regulatory factors, and summarizes the role of multiple signaling pathways during embryonic development. A better understanding of the cardiac NC and its vast regulatory network will provide a deeper insight into the mechanisms of the associated abnormalities, leading to potential therapeutic advancements.

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ROLE OF CARDIAC NEURAL CREST CELLS IN CARDIOVASCULAR DEVELOPMENT

Annual Review of Physiology ◽

10.1146/annurev.physiol.60.1.267 ◽

1998 ◽

Vol 60 (1) ◽

pp. 267-286 ◽

Cited By ~ 187

Author(s):

Tony L. Creazzo ◽

Robert E. Godt ◽

Linda Leatherbury ◽

Simon J. Conway ◽

Margaret L. Kirby

Keyword(s):

Neural Crest ◽

Neural Crest Cells ◽

Cardiovascular Development ◽

Cardiac Neural Crest

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Twist1 performs distinct spatio‐temporal functions in developing cardiac neural crest cells

The FASEB Journal ◽

10.1096/fasebj.25.1_supplement.lb23 ◽

2011 ◽

Vol 25 (S1) ◽

Author(s):

Joshua Wayne Vincentz ◽

Ralston Barnes ◽

Beth Firulli ◽

Douglas Spicer ◽

Anthony Firulli

Keyword(s):

Neural Crest ◽

Neural Crest Cells ◽

Cardiac Neural Crest ◽

Spatio Temporal

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Epigenetic Regulation of Cardiac Neural Crest Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.678954 ◽

2021 ◽

Vol 9 ◽

Author(s):

Shun Yan ◽

Jin Lu ◽

Kai Jiao

Keyword(s):

Neural Crest ◽

Epigenetic Regulation ◽

Heart Development ◽

Congenital Heart ◽

Heart Diseases ◽

Heart Defects ◽

Neural Crest Cells ◽

Abnormal Development ◽

Cardiac Neural Crest ◽

Epigenetic Regulators

The cardiac neural crest cells (cNCCs) is a transient, migratory cell population that contribute to the formation of major arteries and the septa and valves of the heart. Abnormal development of cNCCs leads to a spectrum of congenital heart defects that mainly affect the outflow region of the hearts. Signaling molecules and transcription factors are the best studied regulatory events controlling cNCC development. In recent years, however, accumulated evidence supports that epigenetic regulation also plays an important role in cNCC development. Here, we summarize the functions of epigenetic regulators during cNCC development as well as cNCC related cardiovascular defects. These factors include ATP-dependent chromatin remodeling factors, histone modifiers and DNA methylation modulators. In many cases, mutations in the genes encoding these factors are known to cause inborn heart diseases. A better understanding of epigenetic regulators, their activities and their roles during heart development will ultimately contribute to the development of new clinical applications for patients with congenital heart disease.

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Neural crest cells utilize primary cilia to regulate ventral forebrain morphogenesis via Hedgehog-dependent regulation of oriented cell division

Developmental Biology ◽

10.1016/j.ydbio.2017.09.026 ◽

2017 ◽

Vol 431 (2) ◽

pp. 168-178 ◽

Cited By ~ 2

Author(s):

Elizabeth N. Schock ◽

Samantha A. Brugmann

Keyword(s):

Cell Division ◽

Neural Crest ◽

Primary Cilia ◽

Neural Crest Cells ◽

Oriented Cell Division

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

Development ◽

10.1242/dev.124.2.505 ◽

1997 ◽

Vol 124 (2) ◽

pp. 505-514 ◽

Cited By ~ 14

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.

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

The Journal of Cell Biology ◽

10.1083/jcb.143.6.1725 ◽

1998 ◽

Vol 143 (6) ◽

pp. 1725-1734 ◽

Cited By ~ 170

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.

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