Identification of regulatory elements for MafB expression in the cardiac neural crest

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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Development of cranial nerves in the chick embryo with special reference to the alterations of cardiac branches after ablation of the cardiac neural crest

Anatomy and Embryology ◽

10.1007/bf00186439 ◽

1991 ◽

Vol 183 (5) ◽

Cited By ~ 27

Author(s):

ShigeruC. Kuratani ◽

Sachiko Miyagawa-Tomita ◽

MargaretL. Kirby

Keyword(s):

Chick Embryo ◽

Neural Crest ◽

Special Reference ◽

Cranial Nerves ◽

Cardiac Neural Crest

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Impaired elastic matrix development in the great arteries after ablation of the cardiac neural crest

The Anatomical Record ◽

10.1002/ar.1092260312 ◽

1990 ◽

Vol 226 (3) ◽

pp. 347-359 ◽

Cited By ~ 62

Author(s):

Thomas H. Rosenquist ◽

Arthur C. Beall ◽

Lászlo Módis ◽

Richard Fishman

Keyword(s):

Neural Crest ◽

Elastic Matrix ◽

Cardiac Neural Crest

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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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Abstract 19282: Transient Bone Morphogenic Protein Antagonism Directs Differentiation of Ipscs Into the Cardiac Neural Crest and Ckit+ Myocardial Progenitor Lineages

Circulation ◽

10.1161/circ.132.suppl_3.19282 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Konstantinos E Hatzistergos ◽

Lauro M Takeuchi ◽

Dieter Saur ◽

Barbara Seidler ◽

Susan M Dymecki ◽

...

Keyword(s):

Neural Crest ◽

Signaling Pathway ◽

Progenitor Cell ◽

Embryoid Bodies ◽

Cardiac Neural Crest ◽

Specific Induction ◽

Cre Recombination ◽

Bmp Antagonist ◽

Cardiogenic Differentiation ◽

Cardiac Mesoderm

Introduction: The signaling pathways that govern cKit+ cardiac progenitor cell (CPC) differentiation into cardiomyocytes (CMs) are unknown. Some studies suggest an essential role in cardiomyogenesis, others suggest a minimal CPC contribution. We studied if it is a non-permissive cardiac milieu that minimizes the generation of CMs from CPCs. Hypothesis: Transient BMP antagonism directs the generation of cardiomyocytes from CPCs. Methods: We lineage-traced CPCs using a novel dual-recombinase responsive indicator mice (cKitCreERT2;Wnt1::Flpe;RC::Fela) and iPSCs derived from cKitCreERT2;IRG (iPSCKit) mice. Results: Intersectional genetic fate-mapping of cKitCreERT2;Wnt1:: Flpe;RC::Fela embryos supported that cKit marks Wnt1-expressing cardiac neural crest (CNC) progenitors, emerging at ~E9.5 and contributing a limited number of cardiomyocytes (n=3). We lineage-traced CPCs during stage-specific cardiogenic differentiation of iPSCKit. Ascorbate treatment promoted differentiation of iPSCKit-derived embryoid bodies (EBs) into Nkx2.5+ myocardium, 45.5%±6.7% of which co-expressed the Cre-reporter EGFP (n=154 EBs; 12 preps), suggesting that CPCs encompass fully competent cardiomyogenic progenitors. Noggin (or Dorsomorphin), a BMP antagonist transiently expressed in the heart at E7.5-E8.5 but not during CNC invasion, directed the differentiation of iPSCkit-EBs into Mesp1+/Isl1+/Nkx2.5+ cardiac mesoderm progenitors (p≤0.0001). The same signaling pathway subsequently directed EBs into the cKit+/Wnt1+/Pax3+/Mitf-H+/Isl1+/Nkx2.5+ CNC lineage (p≤0.0001), while suppressing the generation of WT1+/Tbx18+ epicardium (p<0.05). Stage-specific induction of Cre-recombination delineated that iPSCkit-derived CPCs encompass Mesp1–/cKit+/Nkx2.5+ CNC progenitors, which contributed EGFP+ CNC derivatives, including Nkx2-5+ cardiomyocytes, to 60.7%±7.3% of spontaneously beating EBs (n=147 EBs; 12 preps). Conclusions: Our data show that CPCkit are fully competent CNC-derived cardiomyogenic progenitors, whose differentiation to cardiomyocytes is minimized by a latent Noggin-mediated signaling pathway. Therapeutically exploiting CPCkit, provides an important strategy for maximizing myocardial regeneration.

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