Endothelin signaling activates <i>Mef2c</i> expression in the neural crest through a MEF2C-dependent positive-feedback transcriptional pathway

Hu, Jianxin; Verzi, Michael P.; Robinson, Ashley; Tang, Paul Ling-Fung; Hua, Lisa L.; Xu, Shan-Mei; Kwok, Pui‐Yan; Black, Brian L.

doi:10.1242/dev.126391

Cited by 29 publications

(33 citation statements)

References 28 publications

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“…It is therefore unlikely that the lower jaw rescue in nr2f; edn1 mutants is due to increased Bmp signaling. Data from mice suggest that Edn1 drives lower jaw development through a Calmodulin-CamKII-histone deacetylase cascade that de-represses Mef2c, which then transactivates Dlx5/6 expression (Verzi et al, 2007, Hu et al, 2015). One possibility is that Mef2c functions to reverse Nr2f repression of dlx5a/6a , and potentially other mandibular genes, such that, if Nr2f repression is reduced, Edn1-mediated Mef2c transactivation is no longer required.…”

Section: Discussionmentioning

confidence: 99%

Essential Role of Nr2f Nuclear Receptors in Patterning the Vertebrate Upper Jaw

et al. 2018

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The jaw is central to the extensive variety of feeding and predatory behaviors across vertebrates. The bones of the lower but not upper jaw form around an early-developing cartilage template. Whereas Endothelin1 patterns the lower jaw, the factors that specify upper-jaw morphology remain elusive. Here, we identify Nuclear Receptor 2f genes (Nr2fs) as enriched in and required for upper-jaw formation in zebrafish. Combinatorial loss of Nr2fs transforms maxillary components of the upper jaw into lower-jaw-like structures. Conversely, nr2f5 misexpression disrupts lower-jaw development. Genome-wide analyses reveal that Nr2fs repress mandibular gene expression and early chondrogenesis in maxillary precursors. Rescue of lower-jaw defects in endothelin1 mutants by reducing Nr2f dosage further demonstrates that Nr2f expression must be suppressed for normal lower-jaw development. We propose that Nr2fs shape the upper jaw by protecting maxillary progenitors from early chondrogenesis, thus preserving cells for later osteogenesis.

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Section: Discussionmentioning

confidence: 99%

Essential Role of Nr2f Nuclear Receptors in Patterning the Vertebrate Upper Jaw

et al. 2018

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“…Indeed, in the last year, several enhancers have been deleted in mice using 2c CRISPR including those associated with expression of Bcl11a , 94 Blimp1 , 95 Mef2c , 96 Stat5 , 97 Pcdh , 98 Mmp13, 99 Gata3 , 100 and Cebpa . 101 In each case, deletion of the enhancer compromised expression of the associated target gene.…”

Section: Two-component Crisprmentioning

confidence: 99%

A CRISPR Path to Engineering New Genetic Mouse Models for Cardiovascular Research

Miano

Zhu

Lowenstein

2016

ATVB

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Previous efforts to target the mouse genome for the addition, subtraction, or substitution of biologically informative sequences required complex vector design and a series of arduous steps only a handful of labs could master. The facile and inexpensive clustered regularly interspaced short palindromic repeats (CRISPR) method has now superseded traditional means of genome modification such that virtually any lab can quickly assemble reagents for developing new mouse models for cardiovascular research. Here we briefly review the history of CRISPR in prokaryotes, highlighting major discoveries leading to its formulation for genome modification in the animal kingdom. Core components of CRISPR technology are reviewed and updated. Practical pointers for two-component and three-component CRISPR editing are summarized with a number of applications in mice including frameshift mutations, deletion of enhancers and non-coding genes, nucleotide substitution of protein-coding and gene regulatory sequences, incorporation of loxP sites for conditional gene inactivation, and epitope tag integration. Genotyping strategies are presented and topics of genetic mosaicism and inadvertent targeting discussed. Finally, clinical applications and ethical considerations are addressed as the biomedical community eagerly embraces this astonishing innovation in genome editing to tackle previously intractable questions.

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“…Mef2c is a downstream effector of endothelin signaling in mandibular NCC but does not appear to be involved in OFT CNCC, although it is important for heart development and the migration of cells from the anterior/secondary heart field. [51][52][53][54] Edn1 treatment induced Mef2c phosphorylation above the background level visible in the other lanes (4.20 +/−0.57-fold, P < .005). This background, particularly in CNCC, may be attributed to the contaminating cells (with some possibly from the anterior heart field), to some basal level of activity in CNCC or the antibody.…”

Section: Ednra and Cdc42 Work In The Same Pathway In Oft Nccmentioning

confidence: 80%

Cdc42 activation by endothelin regulates neural crest cell migration in the cardiac outflow tract

Fritz¹,

Zhang²,

Ruest³

2019

Developmental Dynamics

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Background: Congenital cardiovascular malformations are the most common birth defects affecting children. Several of these defects occur in structures developing from neural crest cells. One of the key signaling pathways regulating cardiac neural crest cell (CNCC) development involves the endothelin-A receptor (Ednra). However, the exact function of Ednra signaling in CNCC is unknown. Results: The fate mapping of CNCC in Ednra embryos indicated that the migration of these cells is aberrant in the cardiac outflow tract (OFT), but not in the pharyngeal arches. This premature arrest of CNCC migration occurs independently of CNCC proliferation and apoptosis changes and major gene expression changes. Analysis of the Rho family of small GTPases in the mutant embryos revealed that Cdc42 failed to localize normally in the CNCC migrating in the OFT. The inhibition of Cdc42 activity in cultured embryos recapitulated the migratory phenotype observed in Ednra mice. Further analyses revealed that Cdc42 is part of the signaling pathway activated by endothelin specifically in OFT CNCC to control their migration. Conclusions: These results indicated that the activation of Cdc42 by endothelin signaling is important for CNCC migration in the OFT but this pathway is not involved in mandibular or pharyngeal arch artery patterning.K E Y W O R D S cardiovascular malformation, Cdc42, endothelin, fate mapping, migration, neural crest cell

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Endothelin signaling activates Mef2c expression in the neural crest through a MEF2C-dependent positive-feedback transcriptional pathway

Cited by 29 publications

References 28 publications

Essential Role of Nr2f Nuclear Receptors in Patterning the Vertebrate Upper Jaw

Essential Role of Nr2f Nuclear Receptors in Patterning the Vertebrate Upper Jaw

A CRISPR Path to Engineering New Genetic Mouse Models for Cardiovascular Research

Cdc42 activation by endothelin regulates neural crest cell migration in the cardiac outflow tract

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