Genomic control of neural crest identity by signaling systems

通过信号系统对神经嵴特性进行基因组控制

• 批准号: 10165694
• 负责人: Marcos Simoes-Costa
• 金额: $ 35.79万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165694
• 关键词: Address; Affect; Agonist; Animal Model; Back; Binding; Binding Sites; Biological Assay; Birds; Bone Morphogenetic Proteins; Cartilage; Cells; Co-Immunoprecipitations; Complement; Complex; Congenital Abnormality; Craniofacial Abnormalities; Cues; Development; Diagnosis; Disease; Elements; Embryo; Embryonic Development; Enhancers; Ensure; Etiology; Face; Fluorescence; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Genomic Segment; Genomics; Goals; Health; Human; In Vitro; Ligation; Logic; Malignant Neoplasms; Modeling; Molecular; Mutation; Natural regeneration; Neural Crest; Neural Crest Cell; Nuclear; Output; Pathway interactions; Phenotype; Play; Positioning Attribute; Process; Regulator Genes; Regulatory Element; Role; Running; Signal Pathway; Signal Transduction; Signaling Protein; Skeleton; Surveys; System; TFAP2A gene; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Engineering; Tissues; WNT Signaling Pathway; Work; beta catenin; bone; cell type; combinatorial; craniofacial; craniofacial development; disability; embryonic stem cell; experimental study; extracellular; genome-wide; insight; multipotent cell; neural plate; neuroregulation; novel; progenitor; programs; repaired; stem cell differentiation; stem cell population; stem cells; transcriptome; transcriptomics

PROJECT SUMMARY / ABSTRACT The neural crest is an embryonic stem cell population that gives rise to multiple derivatives, including most of the craniofacial skeleton. The formation of neural crest cells is controlled by a gene regulatory network (GRN) that endows these progenitor cells with their unique features, including multipotency and the ability to migrate. This complex molecular program is modulated by extracellular signals that ensure precise spatial control of neural crest specification. In particular, the Wingless (Wnt) signaling pathway has been shown to play a pivotal role in the establishment of craniofacial cell types. Despite the importance of this signaling pathway, only a few direct Wnt targets have been identified within the neural crest GRN. Furthermore, we also lack a mechanistic understanding of how Wnts cooperate with other signaling systems, such as the Bone Morphogenetic Protein (BMP) pathway, during early neural crest development. To identify novel targets of canonical Wnt signaling, we surveyed the genomic occupancy of Wnt nuclear effectors Lef1 and β-catenin in nascent avian neural crest cells. This analysis uncovered multiple neural crest genes that are controlled via tissue-specific Wnt- responsive enhancers. Intriguingly, we found that the genomic regions occupied by both Lef1/β-catenin also contained multiple binding motifs for Smads, the nuclear effectors of BMP signaling. Accordingly, we hypothesize that canonical Wnts cooperate with BMPs to initiate the neural crest gene GRN at the neural plate border. We will test this hypothesis by (a) identifying the direct Wnt target genes in the neural crest GRN; (b) defining how combinatorial input of Wnt and BMP signaling systems affects the output of the neural crest enhancers; and (c) determining how effectors of Wnts and BMPs interact to control gene expression. The overarching goal of this proposal is to define how environmental cues impact gene expression in a genome- wide manner to modulate cell identity. We anticipate that the findings of this proposal will provide a comprehensive model of how enhancers integrate inputs from distinct signaling systems to activate complex transcriptional programs. The mechanisms uncovered in this work will impact not only tissue engineering but also inform upon abnormal shifts in cell identity that are relevant to human health, such as cancer and congenital malformations.

项目摘要/摘要