Neural crest specification and migration independently require NSD3-related lysine methyltransferase activity

Neural crest precursors express genes that cause them to become migratory, multipotent cells, distinguishing them from adjacent stationary neural progenitors in the neurepithelium. Histone methylation spatiotemporally regulates neural crest gene expression; however, the protein methyltransferases active in neural crest precursors are unknown. Moreover, the regulation of methylation during the dynamic process of neural crest migration is unclear. Here we show that the lysine methyltransferase NSD3 is abundantly and specifically expressed in premigratory and migratory neural crest cells. NSD3 expression commences before up-regulation of neural crest genes, and NSD3 is necessary for expression of the neural plate border gene Msx1, as well as the key neural crest transcription factors Sox10, Snail2, Sox9, and FoxD3, but not gene expression generally. Nevertheless, only Sox10 histone H3 lysine 36 dimethylation requires NSD3, revealing unexpected complexity in NSD3-dependent neural crest gene regulation. In addition, by temporally limiting expression of a dominant negative to migratory stages, we identify a novel, direct requirement for NSD3-related methyltransferase activity in neural crest migration. These results identify NSD3 as the first protein methyltransferase essential for neural crest gene expression during specification and show that NSD3-related methyltransferase activity independently regulates migration.

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Segmental origin and migration of neural crest cells in the hindbrain region of the chick embryo

Development ◽

10.1242/dev.113.4.1281 ◽

1991 ◽

Vol 113 (4) ◽

pp. 1281-1291 ◽

Cited By ~ 83

Author(s):

A. Lumsden ◽

N. Sprawson ◽

A. Graham

Keyword(s):

Chick Embryo ◽

Neural Crest ◽

Fate Map ◽

Membrane Probe ◽

Vital Dye ◽

Video Fluorescence Microscopy ◽

Dye Analysis ◽

And Migration ◽

Neural Crest Migration ◽

Branchial Region

A vital dye analysis of cranial neural crest migration in the chick embryo has provided a positional fate map of greater resolution than has been possible using labelled graft techniques. Focal injections of the fluorescent membrane probe DiI were made into the cranial neural folds at stages between 3 and 16 somites. Groups of neuroepithelial cells, including the premigratory neural crest, were labelled by the vital dye. Analysis of whole-mount embryos after 1–2 days further development, using conventional and intensified video fluorescence microscopy, revealed the pathways of crest cells migrating from mesencephalic and rhombencephalic levels of the neuraxis into the subjacent branchial region. The patterns of crest emergence and emigration correlate with the segmented disposition of the rhombencephalon. Branchial arches 1, 2 and 3 are filled by crest cells migrating from rhombomeres 2, 4 and 6 respectively, in register with the cranial nerve entry/exit points in these segments. The three streams of ventrally migrating cells are separated by alternating regions, rhombomeres 3 and 5, which release no crest cells. Rostrally, rhombomere 1 and the caudal mesencephalon also contribute crest to the first arch, primarily to its upper (maxillary) component. Both r3 and r5 are associated with enhanced levels of cell death amongst cells of the dorsal midline, suggesting that crest may form at these levels but is then eliminated. Organisation of the branchial region is thus related by the dynamic process of neural crest immigration to the intrinsic mechanisms that segment the neuraxis.

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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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rad21 Is Involved in Corneal Stroma Development by Regulating Neural Crest Migration

International Journal of Molecular Sciences ◽

10.3390/ijms21207807 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7807

Author(s):

Bi Ning Zhang ◽

Yu Liu ◽

Qichen Yang ◽

Pui Ying Leung ◽

Chengdong Wang ◽

...

Keyword(s):

Gene Expression ◽

Cell Migration ◽

Neural Crest ◽

Corneal Stroma ◽

Neural Crest Cell ◽

Chromosome Conformation ◽

Neural Crest Cell Migration ◽

Neural Crest Migration ◽

Crest Cell ◽

Xenopus Laevis Embryos

Previously, we identified RAD21R450C from a peripheral sclerocornea pedigree. Injection of this rad21 variant mRNA into Xenopus laevis embryos disrupted the organization of corneal stroma fibrils. To understand the mechanisms of RAD21-mediated corneal stroma defects, gene expression and chromosome conformation analysis were performed using cells from family members affected by peripheral sclerocornea. Both gene expression and chromosome conformation of cell adhesion genes were affected in cells carrying the heterozygous rad21 variant. Since cell migration is essential in early embryonic development and sclerocornea is a congenital disease, we studied neural crest migration during cornea development in X. laevis embryos. In X. laevis embryos injected with rad21 mutant mRNA, neural crest migration was disrupted, and the number of neural crest-derived periocular mesenchymes decreased significantly in the corneal stroma region. Our data indicate that the RAD21R450C variant contributes to peripheral sclerocornea by modifying chromosome conformation and gene expression, therefore disturbing neural crest cell migration, which suggests RAD21 plays a key role in corneal stroma development.

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GSK3 Controls Migration of the Neural Crest Lineage

10.1101/243170 ◽

2018 ◽

Author(s):

Sandra G. Gonzalez Malagon ◽

Anna M. Lopez Muñoz ◽

Daniel Doro ◽

Triòna G. Bolger ◽

Evon Poon ◽

...

Keyword(s):

Cell Migration ◽

Neural Crest ◽

Glycogen Synthase ◽

Neuroblastoma Cells ◽

Neural Crest Cells ◽

Anaplastic Lymphoma ◽

Neural Crest Development ◽

And Migration ◽

Neural Crest Migration

AbstractMigration of the neural crest lineage is critical to its physiological function. Mechanisms controlling neural crest migration are comparatively unknown, due to difficulties accessing this cell population in vivo. Here, we uncover novel requirements of glycogen synthase kinase 3 (GSK3) in regulating the neural crest. We demonstrate that GSK3 is tyrosine phosphorylated (pY) in neural crest cells and that this activation depends on anaplastic lymphoma kinase (ALK), a protein associated with neuroblastoma. Consistent with this, neuroblastoma cells with pathologically increased ALK activity express high levels of pY-GSK3 and migration of these cells can be inhibited by GSK3 or ALK blockade. In normal neural crest cells, loss of GSK3 leads to increased pFAK and misregulation of Rac1 and lamellipodin, key regulators of cell migration. Genetic reduction of GSK-3 results in failure of migration. All together, this work identifies a role for GSK3 in cell migration during neural crest development and cancer.

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