MSX1-induced neural crest-like phenotype in human melanocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE56957 | GEO | 2016/09/30
SECONDARY ACCESSION(S): PRJNA245072
REPOSITORIES: GEO
Similar Datasets
Project description:Melanocytes are pigment-producing cells of neural crest origin responsible for protecting the skin against UV-irradiation. Melanocyte dysfunction leads to pigmentation defects including albinism, vitiligo, and piebaldism and is a key feature of systemic pathologies such as Hermansky-Pudlak (HP) and Chediak-Higashi (CH) Syndromes. Pluripotent stem cell technology offers a novel approach for studying human melanocyte development and disease. Here we report that timed exposure to activators of WNT, BMP and EDN3 signaling triggers the sequential induction of neural crest and melanocyte precursor fates under dual-SMAD inhibition conditions. Using a SOX10::GFP hESC reporter line, we demonstrate that the temporal onset of WNT activation is particularly critical for human neural crest induction. Surprisingly, suppression of BMP signaling does reduce neural crest yield. Subsequent differentiation of hESC-derived melanocyte precursors under defined conditions yields pure populations of pigmented cells matching the molecular and functional properties of adult melanocytes. Melanocytes from patient-specific iPSCs faithfully reproduce the ultrastructural features of the HP- and CH-specific pigmentation defects with minimal variability across lines. Our data define a highly specific requirement for WNT signaling during neural crest induction and enable the generation of pure populations of hiPSC-derived melanocytes for faithful modeling of human pigmentation disorders. Total RNA obtained from embryonic stem cells (ESCs), ESC-derived melanocyte progenitors, ESC-derived mature melanocytes, primary melanocytes, and disease-specific induced pluripotent stem cell-derived melanocytes.
2013-06-01 | E-GEOD-45226 | biostudies-arrayexpress
Project description:Melanocytes are pigment-producing cells of neural crest origin responsible for protecting the skin against UV-irradiation. Melanocyte dysfunction leads to pigmentation defects including albinism, vitiligo, and piebaldism and is a key feature of systemic pathologies such as Hermansky-Pudlak (HP) and Chediak-Higashi (CH) Syndromes. Pluripotent stem cell technology offers a novel approach for studying human melanocyte development and disease. Here we report that timed exposure to activators of WNT, BMP and EDN3 signaling triggers the sequential induction of neural crest and melanocyte precursor fates under dual-SMAD inhibition conditions. Using a SOX10::GFP hESC reporter line, we demonstrate that the temporal onset of WNT activation is particularly critical for human neural crest induction. Surprisingly, suppression of BMP signaling does reduce neural crest yield. Subsequent differentiation of hESC-derived melanocyte precursors under defined conditions yields pure populations of pigmented cells matching the molecular and functional properties of adult melanocytes. Melanocytes from patient-specific iPSCs faithfully reproduce the ultrastructural features of the HP- and CH-specific pigmentation defects with minimal variability across lines. Our data define a highly specific requirement for WNT signaling during neural crest induction and enable the generation of pure populations of hiPSC-derived melanocytes for faithful modeling of human pigmentation disorders.
2013-06-01 | GSE45226 | GEO
Project description:Melanocytes are pigment-producing cells of neural crest origin responsible for protecting the skin against UV-irradiation. Melanocyte dysfunction leads to pigmentation defects including albinism, vitiligo, and piebaldism and is a key feature of systemic pathologies such as Hermansky-Pudlak (HP) and Chediak-Higashi (CH) Syndromes. Pluripotent stem cell technology offers a novel approach for studying human melanocyte development and disease. Here we report that timed exposure to activators of WNT, BMP and EDN3 signaling triggers the sequential induction of neural crest and melanocyte precursor fates under dual-SMAD inhibition conditions. Using a SOX10::GFP hESC reporter line, we demonstrate that the temporal onset of WNT activation is particularly critical for human neural crest induction. Surprisingly, suppression of BMP signaling does reduce neural crest yield. Subsequent differentiation of hESC-derived melanocyte precursors under defined conditions yields pure populations of pigmented cells matching the molecular and functional properties of adult melanocytes. Melanocytes from patient-specific iPSCs faithfully reproduce the ultrastructural features of the HP- and CH-specific pigmentation defects with minimal variability across lines. Our data define a highly specific requirement for WNT signaling during neural crest induction and enable the generation of pure populations of hiPSC-derived melanocytes for faithful modeling of human pigmentation disorders. Total RNA obtained from a timecourse of Dual SMAD Inhibition (DSi), Neural Crest (NC), and Melanocyte (BE) differentiation of human embryonic stem cells in triplicate.
2013-06-01 | E-GEOD-45223 | biostudies-arrayexpress
Project description:The mandible of the jawed vertebrate is derived from the mandibular process of the first pharyngeal arch of the early embryo. The first pharyngeal arch consists of cells from all three germ layers, with the neural crest giving rise to all the skeletal elements of the mandible. The correct patterning of the neural crest cells by spatially and temporally controlled expression of various transcription factors during mandible development is crucial for the proper morphogenesis of the lower jaw. Msx family genes encode transcription factors which contain the conserved homeodomain. Among the three members of Msx genes, Msx1 and Msx2 are expressed in the neural crest and epithelium of distal mandibular process during early embryonic development with partially overlapped expression patterns. Msx1-/- mouse embryos develop multiple craniofacial developmental defects including tooth agenesis, cleft palate, and hypoplastic mandible. Although no jaw defects were observed in Msx2-/- mouse embryos, Msx1-/-Msx2-/- mouse embryos exhibit significantly severer mandibular defects compared to Msx1-/- mouse embryos, suggesting a partial functional redundancy between the two genes in mandible development. Besides the direct roles of Msx1 and Msx2 in the development of the mandibular neural crest, the phenotypes of Msx1-/-Msx2-/- may also contributed by secondary impacts from defective pre-migrative neural crest and non-neural crest tissues. Here we performed the gene expression profiling by RNA-seq in the distal mandibular processes of Msx1f/f;Msx2f/f;Hand2-Cre and Msx1f/+;Msx2f/f;Hand2-Cre embryos at E10.75, the former developed distally truncated mandible at later stages while the latter served as morphologically normal littermate control. Comparing the gene expression profiles of the two will give us insight into the functions of Msx1 and Msx2 expressed in mandibular neural crest cells in the development of the mandible.
2024-01-10 | GSE222566 | GEO
Project description:Neuroblastoma is an embryonal tumour of the peripheral sympathetic nervous system (SNS). One of the master regulator genes for peripheral SNS differentiation, the homeobox transcription factor PHOX2B, is mutated in familiar and sporadic neuroblastomas. Here we report that inducible expression of PHOX2B in the neuroblastoma cell line SJNB-8 down-regulates MSX1, a homeobox gene important for embryonic neural crest development. Inducible expression of MSX1 in SJNB-8 caused inhibition of both cell proliferation and colony formation in soft agar. Affymetrix micro- array and Northern blot analysis demonstrated that MSX1 strongly up-regulated the Delta-Notch pathway. These experiments describe for the first time regulation of the Delta-Notch pathway by MSX1, and connect these genes to the PHOX2B oncogene, indicative of a role in neuroblastoma biology. Keywords: Delta, Notch, MSX1, neuroblastoma, PHOX2B
2008-10-15 | GSE9339 | GEO
Project description:Mutations in the gene encoding transcription factor TFAP2A result in pigmentation anomalies in model organisms and premature hair graying in humans. However, the pleiotropic functions of TFAP2A and its redundantly-acting paralogs have made the precise contribution of TFAP2-type activity to melanocyte differentiation unclear. Defining this contribution may help to explain why TFAP2A expression is reduced in advanced-stage melanoma compared to benign nevi. To identify genes with TFAP2A-dependent expression in melanocytes, we profile zebrafish tissue and mouse melanocytes deficient in Tfap2a, and find that expression of a small subset of genes underlying pigmentation phenotypes is TFAP2A-dependent, including Dct, Mc1r, Mlph, and Pmel. We then conduct TFAP2A ChIP-seq in mouse and human melanocytes and find that a much larger subset of pigmentation genes is associated with active regulatory elements bound by TFAP2A. These elements are also frequently bound by MITF, which is considered the “master regulator” of melanocyte development. For example, the promoter of TRPM1 is bound by both TFAP2A and MITF, and we show that the activity of a minimal TRPM1 promoter is lost upon deletion of the TFAP2A binding sites. However, the expression of Trpm1 is not TFAP2A-dependent, implying that additional TFAP2 paralogs function redundantly to drive melanocyte differentiation, which is consistent with previous results from zebrafish. Paralogs Tfap2a and Tfap2b are both expressed in mouse melanocytes, and we show that mouse embryos with Wnt1-Cre-mediated deletion of Tfap2a and Tfap2b in the neural crest almost completely lack melanocytes but retain neural crest-derived sensory ganglia. These results suggest that TFAP2 paralogs, like MITF, are also necessary for induction of the melanocyte lineage. Finally, we observe a genetic interaction between tfap2a and mitfa in zebrafish, but find that artificially elevating expression of tfap2a does not increase levels of melanin in mitfa hypomorphic or loss-of-function mutants. Collectively, these results show that TFAP2 paralogs, operating alongside lineage-specific transcription factors such as MITF, directly regulate effectors of terminal differentiation in melanocytes. In addition, they suggest that TFAP2A activity, like MITF activity, has the potential to modulate the phenotype of melanoma cells.
2017-02-23 | GSE67555 | GEO
Project description:Melanocytes are pigment-producing cells of neural crest origin responsible for protecting the skin against UV-irradiation. Melanocyte dysfunction leads to pigmentation defects including albinism, vitiligo, and piebaldism and is a key feature of systemic pathologies such as Hermansky-Pudlak (HP) and Chediak-Higashi (CH) Syndromes. Pluripotent stem cell technology offers a novel approach for studying human melanocyte development and disease. Here we report that timed exposure to activators of WNT, BMP and EDN3 signaling triggers the sequential induction of neural crest and melanocyte precursor fates under dual-SMAD inhibition conditions. Using a SOX10::GFP hESC reporter line, we demonstrate that the temporal onset of WNT activation is particularly critical for human neural crest induction. Surprisingly, suppression of BMP signaling does reduce neural crest yield. Subsequent differentiation of hESC-derived melanocyte precursors under defined conditions yields pure populations of pigmented cells matching the molecular and functional properties of adult melanocytes. Melanocytes from patient-specific iPSCs faithfully reproduce the ultrastructural features of the HP- and CH-specific pigmentation defects with minimal variability across lines. Our data define a highly specific requirement for WNT signaling during neural crest induction and enable the generation of pure populations of hiPSC-derived melanocytes for faithful modeling of human pigmentation disorders.
2013-06-01 | GSE45223 | GEO
Project description:MSX1-induced neural crest-like phenotype in human melanocytes
| PRJNA245072 | ENA
Project description:The first step in the development of human colorectal cancer (CRC) is the aberrant hyperactivation of the Wnt signaling pathway, predominantly caused by inactivating mutations in the adenomatous polyposis coli (APC) gene encoding an essential tumor suppressor. In order to identify genes affected by Apc loss, expression profiling of intestinal epithelium isolated from mice harboring the conditional allele of the gene was performed. The gene encoding transcriptional factor msh homeobox 1 (Msx1) displayed robust upregulation upon Apc inactivation. Subsequently, the expression pattern of human MSX1 was examined in a collection of colonic tumors. The MSX1 mRNA level was increased in all types of human intestinal neoplasia tested. In order to identify genes affected by MSX1 loss, expression profiling of human colorectal cancer cells SW620 upon MSX1 gene depletion was performed.
2019-11-01 | E-MTAB-6928 | biostudies-arrayexpress
Project description:The first step in the development of human colorectal cancer is the aberrant hyperactivation of the Wnt signaling pathway, predominantly caused by inactivating mutations in the adenomatous polyposis coli (Apc) gene encoding an essential tumor suppressor. The gene encoding transcriptional factor msh homeobox 1 (Msx1) displayed robust upregulation upon Apc inactivation in intestinal epithelium isolated in mice harboring the conditional allele of the Apc gene. To identify the gene signature in the small intestine upon Msx1 depletion, small intestinal epithelium from mice harboring conditional alleles of Apc and Msx1 was isolated and the gene expression profile was compared with control mice harboring the conditional allele of Apc only.
2019-11-01 | E-MTAB-6930 | biostudies-arrayexpress