scholarly journals Regulation of melanocyte development by ligand-dependent BMP signaling underlies oncogenic BMP signaling in melanoma

2019 ◽  
Author(s):  
Alec K. Gramann ◽  
Arvind M. Venkatesan ◽  
Melissa Guerin ◽  
Craig J. Ceol
Keyword(s):  
Neural Crest ◽  
Pigment Cell ◽  
Terminal Differentiation ◽  
Melanoma Cells ◽  
Cell Development ◽  
Bmp Signaling ◽  
Pigment Cells ◽  
Cell Type ◽  
Neural Crest Development ◽  
Direct Regulation

AbstractPreventing terminal differentiation is important in the development and progression of many cancers including melanoma. Recent identification of the BMP ligand GDF6 as a novel melanoma oncogene showed GDF6-activated BMP signaling suppresses differentiation of melanoma cells. Previous studies have identified roles for GDF6 orthologs during early embryonic and neural crest development, but have not identified direct regulation of melanocyte development by GDF6. Here, we investigate the BMP ligand gdf6a, a zebrafish ortholog of human GDF6, during the development of melanocytes from the neural crest. We establish that the loss of gdf6a or inhibition of BMP signaling during neural crest development disrupts normal pigment cell development, leading to an increase in the number of melanocytes and a corresponding decrease in iridophores, another neural crest-derived pigment cell type in zebrafish. This shift occurs as pigment cells arise from the neural crest and depends on mitfa, an ortholog of MITF, a key regulator of melanocyte development that is also targeted by oncogenic BMP signaling. Together, these results indicate that the oncogenic role ligand-dependent BMP signaling plays in suppressing differentiation in melanoma is a reiteration of its physiological roles during melanocyte development.

scholarly journals Regulation of zebrafish melanocyte development by ligand-dependent BMP signaling

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Alec K Gramann ◽  
Arvind M Venkatesan ◽  
Melissa Guerin ◽  
Craig J Ceol
Keyword(s):  
Neural Crest ◽  
Pigment Cell ◽  
Terminal Differentiation ◽  
Melanoma Cells ◽  
Cell Development ◽  
Bmp Signaling ◽  
Pigment Cells ◽  
Cell Type ◽  
Neural Crest Development ◽  
Direct Regulation

Preventing terminal differentiation is important in the development and progression of many cancers including melanoma. Recent identification of the BMP ligand GDF6 as a novel melanoma oncogene showed GDF6-activated BMP signaling suppresses differentiation of melanoma cells. Previous studies have identified roles for GDF6 orthologs during early embryonic and neural crest development, but have not identified direct regulation of melanocyte development by GDF6. Here, we investigate the BMP ligand gdf6a, a zebrafish ortholog of human GDF6, during the development of melanocytes from the neural crest. We establish that the loss of gdf6a or inhibition of BMP signaling during neural crest development disrupts normal pigment cell development, leading to an increase in the number of melanocytes and a corresponding decrease in iridophores, another neural crest-derived pigment cell type in zebrafish. This shift occurs as pigment cells arise from the neural crest and depends on mitfa, an ortholog of MITF, a key regulator of melanocyte development that is also targeted by oncogenic BMP signaling. Together, these results indicate that the oncogenic role ligand-dependent BMP signaling plays in suppressing differentiation in melanoma is a reiteration of its physiological roles during melanocyte development.

scholarly journals An analysis of pigment cell development in the periodic albino mutant of Xenopus

Development ◽  
1979 ◽  
Vol 52 (1) ◽  
pp. 165-170
Author(s):  
Gillian J. MacMillan
Keyword(s):  
Cell Differentiation ◽  
Neural Crest ◽  
Pigment Cell ◽  
Cell Development ◽  
Pigment Cells ◽  
Wild Type ◽  
Mutant Effect ◽  
Albino Mutant ◽  
Cells Cultured ◽  
Periodic Albino

The periodic albino mutant (apap) of Xenopus in which the development of melanophoresis impaired, is further reported here to possess an aberrant pattern of iridophore differentiation. The development of mutant and wild-type neural crest explants isolated in vesicles derived from tissues from identical and different genotypes was examined to determine if the mutant effect resides in the pigment cells or is mediated by the environmental tissues. Mutant melanophores and iridophores cultured in either mutant or wild-type tissues exhibited mutant patterns of differentiation. Wild-type pigment cells cultured in both wild-type and mutant tissues exhibited wild-type patterns of differentiation. Hence the mutation affects the capacities of melanoblasts and iridoblasts to differentiate but not the ability of the environmental tissues to support pigment cell differentiation.

scholarly journals Review: The Role of Wnt/β-Catenin Signalling in Neural Crest Development in Zebrafish

2021 ◽  
Vol 9 ◽  
Author(s):  
Gemma Sutton ◽  
Robert N. Kelsh ◽  
Steffen Scholpp
Keyword(s):  
Neural Crest ◽  
Pigment Cell ◽  
Model Organism ◽  
Neural Plate ◽  
The Body ◽  
Signalling Pathway ◽  
Border Region ◽  
Pigment Cells ◽  
Neural Plate Border

The neural crest (NC) is a multipotent cell population in vertebrate embryos with extraordinary migratory capacity. The NC is crucial for vertebrate development and forms a myriad of cell derivatives throughout the body, including pigment cells, neuronal cells of the peripheral nervous system, cardiomyocytes and skeletogenic cells in craniofacial tissue. NC induction occurs at the end of gastrulation when the multipotent population of NC progenitors emerges in the ectodermal germ layer in the neural plate border region. In the process of NC fate specification, fate-specific markers are expressed in multipotent progenitors, which subsequently adopt a specific fate. Thus, NC cells delaminate from the neural plate border and migrate extensively throughout the embryo until they differentiate into various cell derivatives. Multiple signalling pathways regulate the processes of NC induction and specification. This review explores the ongoing role of the Wnt/β-catenin signalling pathway during NC development, focusing on research undertaken in the Teleost model organism, zebrafish (Danio rerio). We discuss the function of the Wnt/β-catenin signalling pathway in inducing the NC within the neural plate border and the specification of melanocytes from the NC. The current understanding of NC development suggests a continual role of Wnt/β-catenin signalling in activating and maintaining the gene regulatory network during NC induction and pigment cell specification. We relate this to emerging models and hypotheses on NC fate restriction. Finally, we highlight the ongoing challenges facing NC research, current gaps in knowledge, and this field’s potential future directions.

nacre encodes a zebrafish microphthalmia-related protein that regulates neural-crest-derived pigment cell fate

Development ◽  
1999 ◽  
Vol 126 (17) ◽  
pp. 3757-3767 ◽  
Author(s):  
J.A. Lister ◽  
C.P. Robertson ◽  
T. Lepage ◽  
S.L. Johnson ◽  
D.W. Raible
Keyword(s):  
Transcription Factor ◽  
Retinal Pigment Epithelium ◽  
Neural Crest ◽  
Cell Fate ◽  
Pigment Cell ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Pigment Cells ◽  
Evolutionary Divergence ◽  
Wild Type

We report the isolation and identification of a new mutation affecting pigment cell fate in the zebrafish neural crest. Homozygous nacre (nac(w2)) mutants lack melanophores throughout development but have increased numbers of iridophores. The non-crest-derived retinal pigment epithelium is normal, suggesting that the mutation does not affect pigment synthesis per se. Expression of early melanoblast markers is absent in nacre mutants and transplant experiments suggested a cell-autonomous function in melanophores. We show that nac(w2) is a mutation in a zebrafish gene encoding a basic helix-loop-helix/leucine zipper transcription factor related to microphthalmia (Mitf), a gene known to be required for development of eye and crest pigment cells in the mouse. Transient expression of the wild-type nacre gene restored melanophore development in nacre(−/−) embryos. Furthermore, misexpression of nacre induced the formation of ectopic melanized cells and caused defects in eye development in wild-type and mutant embryos. These results demonstrate that melanophore development in fish and mammals shares a dependence on the nacre/Mitf transcription factor, but that proper development of the retinal pigment epithelium in the fish is not nacre-dependent, suggesting an evolutionary divergence in the function of this gene.

The zebrafish colourless gene regulates development of non-ectomesenchymal neural crest derivatives

Development ◽  
2000 ◽  
Vol 127 (3) ◽  
pp. 515-525 ◽  
Author(s):  
R.N. Kelsh ◽  
J.S. Eisen
Keyword(s):  
Nervous System ◽  
Neural Crest ◽  
Cell Types ◽  
Pigment Cells ◽  
Specific Cell ◽  
Zebrafish Embryos ◽  
Craniofacial Skeleton ◽  
Cell Fates ◽  
Peripheral Neurons ◽  
Neural Crest Development

Neural crest forms four major categories of derivatives: pigment cells, peripheral neurons, peripheral glia, and ectomesenchymal cells. Some early neural crest cells generate progeny of several fates. How specific cell fates become specified is still poorly understood. Here we show that zebrafish embryos with mutations in the colourless gene have severe defects in most crest-derived cell types, including pigment cells, neurons and specific glia. In contrast, craniofacial skeleton and medial fin mesenchyme are normal. These observations suggest that colourless has a key role in development of non-ectomesenchymal neural crest fates, but not in development of ectomesenchymal fates. Thus, the cls mutant phenotype reveals a segregation of ectomesenchymal and non-ectomesenchymal fates during zebrafish neural crest development. The combination of pigmentation and enteric nervous system defects makes colourless mutations a model for two human neurocristopathies, Waardenburg-Shah syndrome and Hirschsprung's disease.

The control of pigment cell pattern formation in the California newt, Taricha torosa

Development ◽  
1986 ◽  
Vol 97 (1) ◽  
pp. 141-168
Author(s):  
R. P. Tucker ◽  
C. A. Erickson
Keyword(s):  
Neural Crest ◽  
Pigment Cell ◽  
Contact Inhibition ◽  
Pigment Cells ◽  
Lateral Plate Mesoderm ◽  
Lateral Plate ◽  
Pronephric Duct ◽  
Taricha Torosa ◽  
Dorsal Stripe

Neural crest-derived pigment cells form species-specific patterns of pigmentation in amphibian embryos. We have characterized the appearance and changes in pigment cell distribution in the embryos of the California newt, Taricha torosa. Black melanophores first appear scattered over the surface of the somites intermingled with yellow xanthophores in stage 34/35 embryos. The melanophores then migrate either dorsally to form a dorsal stripe at the apex of the somites or ventrally along the intersomitic furrows to form a midbody stripe at the somite—lateral plate mesoderm border. Xanthophores remain between the two melanophore stripes and are also found in the dorsal fin and head. The formation of the dorsal stripe coincides with a change in melanophore tissue affinity from the surface of the somites to the subectodermal extracellular matrix (ECM). The latter substratum is the location of the cue used to organize the dorsal stripe. In addition, melanophores become elongate and highly arborized, which would allow them to extend to the region where the dorsal stripe forms. In contrast, xanthophores do not form long processes in vitro. This suggests that the ability of melanophores but not xanthophores to search for a cue at the apex of the somites may account in part for the segregation of these cells types. Melanophores and xanthophores are trapped to form the midbody stripe by the pronephric duct, which is located just beneath the ectoderm at the bases of the intersomitic furrows. Ablation of the duct prevents formation of the midbody stripe, although melanophores and xanthophores still fail to migrate ventrally over the lateral plate mesoderm. Melanophores grafted to the ventral midline fail to leave the confines of the donor tissue. This suggests that a factor in the lateral plate mesoderm in addition to the pronephric duct is inhibiting further ventral migration. There is no gross morphological difference in the organization of the subectodermal ECM dorsal and ventral to the pronephric duct as revealed by alcian blue, ruthenium red and staining with antibodies to fibronectin. We also conclude that the directed dispersal of the neural crest into the space between the somites and ectoderm is due to contact inhibition of cell movement, since T. torosa neural crest cells demonstrate contact inhibition in vitro and there are enough cells in the lateral migratory spaces to make contact events likely during dispersal.

Msx2is an immediate downstream effector ofPax3in the development of the murine cardiac neural crest

Development ◽  
2002 ◽  
Vol 129 (2) ◽  
pp. 527-538 ◽  
Author(s):  
Stanford J. Kwang ◽  
Sean M. Brugger ◽  
Arthur Lazik ◽  
Amy E. Merrill ◽  
Lan-Ying Wu ◽  
...  
Keyword(s):  
Neural Crest ◽  
Cardiac Development ◽  
Homeobox Gene ◽  
Bmp Signaling ◽  
Gene Migration ◽  
Cardiac Neural Crest ◽  
Molecular Approaches ◽  
Pax3 Gene ◽  
Downstream Effector ◽  
Neural Crest Development

The neural crest plays a crucial part in cardiac development. Cells of the cardiac subpopulation of cranial neural crest migrate from the hindbrain into the outflow tract of the heart where they contribute to the septum that divides the pulmonary and aortic channels. In Splotch mutant mice, which lack a functional Pax3 gene, migration of cardiac neural crest is deficient and aorticopulmonary septation does not occur. Downstream genes through which Pax3 regulates cardiac neural crest development are unknown. Here, using a combination of genetic and molecular approaches, we show that the deficiency of cardiac neural crest development in the Splotch mutant is caused by upregulation of Msx2, a homeobox gene with a well-documented role as a regulator of BMP signaling. We provide evidence, moreover, that Pax3 represses Msx2 expression via a direct effect on a conserved Pax3 binding site in the Msx2 promoter. These results establish Msx2 as an effector of Pax3 in cardiac neural crest development.

scholarly journals Thyroid hormone regulates distinct paths to maturation in pigment cell lineages

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Lauren M Saunders ◽  
Abhishek K Mishra ◽  
Andrew J Aman ◽  
Victor M Lewis ◽  
Matthew B Toomey ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Neural Crest ◽  
Developmental Trajectories ◽  
Pigment Cell ◽  
Cell Lineage ◽  
Population Expansion ◽  
Cell Types ◽  
Pigment Cells ◽  
Stripe Pattern ◽  
Yellow Orange

Thyroid hormone (TH) regulates diverse developmental events and can drive disparate cellular outcomes. In zebrafish, TH has opposite effects on neural crest derived pigment cells of the adult stripe pattern, limiting melanophore population expansion, yet increasing yellow/orange xanthophore numbers. To learn how TH elicits seemingly opposite responses in cells having a common embryological origin, we analyzed individual transcriptomes from thousands of neural crest-derived cells, reconstructed developmental trajectories, identified pigment cell-lineage specific responses to TH, and assessed roles for TH receptors. We show that TH promotes maturation of both cell types but in distinct ways. In melanophores, TH drives terminal differentiation, limiting final cell numbers. In xanthophores, TH promotes accumulation of orange carotenoids, making the cells visible. TH receptors act primarily to repress these programs when TH is limiting. Our findings show how a single endocrine factor integrates very different cellular activities during the generation of adult form.

Skeletal and pigment cell defects in thelockjaw mutant reveal multiple roles for zebrafishtfap2a in neural crest development

2003 ◽  
Vol 229 (1) ◽  
pp. 87-98 ◽  
Author(s):  
Robert D. Knight ◽  
Yashar Javidan ◽  
Sarah Nelson ◽  
Tailin Zhang ◽  
Thomas Schilling
Keyword(s):  
Neural Crest ◽  
Pigment Cell ◽  
Multiple Roles ◽  
Neural Crest Development

scholarly journals Zebrafish pigment cells develop directly from persistent highly multipotent progenitors.

2021 ◽  
Author(s):  
Masataka Nikaido ◽  
Tatiana Subkhankulova ◽  
Leonid A. Uroshlev ◽  
Artem J. Kasianov ◽  
Karen Camargo Sosa ◽  
...  
Keyword(s):  
Pigment Cell ◽  
Transcriptional Profiling ◽  
Cell Types ◽  
Cell Development ◽  
Lineage Tracing ◽  
Pigment Cells ◽  
Multipotent Stem Cells ◽  
Multipotent Progenitors ◽  
Fate Restriction

Neural crest cells (NCCs) are highly multipotent stem cells. A long-standing controversy exists over the mechanism of NCC fate specification, specifically regarding the presence and potency of intermediate progenitors. The direct fate restriction (DFR) model, based on early in vivo clonal studies, hypothesised that intermediates are absent and that migrating cells maintain full multipotency. However, most authors favour progressive fate restriction (PFR) models, with fully multipotent early NCCs (ENCCs) transitioning to partially-restricted intermediates before committing to individual fates. Here, single cell transcriptional profiling of zebrafish pigment cell development leads to us proposing a Cyclical Fate Restriction mechanism of NCC development that reconciles the DFR and PFR models. Our clustering of single NCC Nanostring transcriptional profiles identifies only broadly multipotent intermediate states between ENCCs and differentiated melanocytes and iridophores. Leukocyte tyrosine kinase (Ltk) marks the multipotent progenitor and iridophores, consistent with biphasic ltk expression. Ltk inhibitor and constitutive activation studies support expression at an early multipotent stage, whilst lineage-tracing of ltk-expressing cells reveals their multipotency extends beyond pigment cell-types to neural fates. We conclude that pigment cell development does not involve a conventional PFR mechanism, but instead occurs directly and more dynamically from a broadly multipotent intermediate state.

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