Molecular Interactions during Neural Crest Formation

神经嵴形成过程中的分子相互作用

• 批准号: 10458050
• 负责人: MARTIN I. GARCIA-CASTRO
• 金额: $ 48.4万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458050
• 关键词: Address; Amaze; Animal Model; Anterior; Area; Binding; Birds; CRISPR/Cas technology; Candidate Disease Gene; Cartilage; Cell Lineage; Cells; Chick; Chick Embryo; Clustered Regularly Interspaced Short Palindromic Repeats; Congenital Abnormality; Development; Dorsal; Embryo; Embryology; Embryonic Development; Endothelin; Epithelial; Erinaceidae; Event; Face; Family; Female; Fibroblast Growth Factor; Gene Expression Profile; Genetic; Genetic Transcription; Goals; Human; In Situ Hybridization; In Vitro; Knowledge; Ligands; MADH2 gene; MADH3 gene; Malignant Neoplasms; Mediating; Mesenchymal; Modeling; Molecular; Neural Crest; Neural Crest Cell; Neural Fold; Neural tube; Neuroglia; Neurons; Nodal; Output; Pathology; Pathway interactions; Peripheral Nervous System; Play; Pluripotent Stem Cells; Population; Process; Research; Role; Signal Induction; Signal Pathway; Signal Transduction; Signaling Molecule; Small Interfering RNA; Testing; Time; Transforming Growth Factor beta; Tretinoin; Vertebrates; WNT Signaling Pathway; Work; base; cell type; combinatorial; craniofacial bone; experimental study; human model; improved; in vivo; innovation; knock-down; loss of function; male; melanocyte; melanoma; migration; neural model; neural plate; notch protein; novel; orofacial cleft; programs; rare condition; receptor; transcriptome sequencing; vertebrate embryos

Project Summary/Abstract. Neural crest cells (NC) are unique to vertebrates, arise early in development, emigrate from the dorsal aspect of the neural tube, and differentiate into a plethora of derivatives throughout the body, contributing neurons and glia of the peripheral nervous system, melanocytes, and craniofacial bone and cartilage amongst other derivatives. Failed NC development is associated with a large number of conditions known as Neurocristopathies, which include common orofacial clefts, aggressive cancers and rare syndromes. The long term goal of this research program is to advance our understanding of the earliest signaling events responsible for the formation of the NC. Currently signaling by WNT, FGF and BMP are amongst a few of key inputs recognized to be critical for the formation of NC, yet our understanding of the molecular mechanisms by which they execute their effects remain limited. To improve our knowledge of this events, it is critical to identify the effectors modulated by these pathways and to characterize their effects. The objectives of this proposal are: 1) to establish and characterize for the first time the role of TGFb /SMAD2-SMAD3 signaling during early facets of NC formation, prior to their allocation into the neural tube, migration or differentiation; and 2) to identify the effectors of the WNT and/or TGFb and characterize their role during early NC formation. Our Hypotheses are that the TGFb /SMAD2-SMAD3 signaling is required to launch the earliest events in NC formation, and that a combination of TGFb and WNT responsive molecules direct the specific acquisition of the NC lineage. To address these hypotheses our proposal is guided by 3 specific aims: 1) to demonstrate the requirement and contribution of the TGFb /SMAD2-SMAD3 signaling during early facets of NC formation, 2) to identify novel candidate effectors of WNT and/or TGFb and characterize their specific contributions to the acquisition of the NC fate, and 3) to assess their function in vivo in a vertebrate embryo. This innovative proposal takes advantage of a robust model of human NC formation based in pluripotent stem cells and classic chick embryology to, for the first time address the possible contribution of TGFb signaling (not BMPs) during this process and pursues an integrative approach addressing the combinatorial signaling of WNT and TGFb. The proposal is significant because the gains in this area will have impact in key aspects of fate acquisition and differentiation applicable to other cell types, and should improve our capacity to manage the many pathologies associated with NC.

项目摘要/摘要。 神经脊细胞(NC)是脊椎动物所特有的，发育早期，从脊椎动物的背侧迁徙而来。 神经管，并在全身分化为过多的衍生品，贡献神经元和胶质细胞 外周神经系统、黑素细胞、头面部骨骼和软骨等衍生产品。 NC开发失败与大量称为神经发育不良的疾病有关，这些疾病 包括常见的口裂、侵袭性癌症和罕见综合征。这项研究的长期目标是 程序是为了推进我们对NC形成的最早信号事件的理解。 目前，WNT、成纤维细胞生长因子和BMP的信号转导是公认的几个关键输入信号之一，它们对 NC的形成，但我们对它们执行其影响的分子机制的理解仍然存在 有限的。为了提高我们对这一事件的了解，识别受这些通路调制的效应器是至关重要的 并描述它们的影响。本提案的目标是：1)建立和描述 首次研究了TGFb/Smad2-Smad3信号在NC形成早期的作用，在它们被分配之前 进入神经管、迁移或分化；以及2)确定WNT和/或TGFb的效应器和 描述它们在NC形成早期所扮演的角色。我们的假设是TGFb/Smad2-Smad3信号 需要在NC队形中启动最早的事件，并且TGFb和WNT的组合响应 分子指导NC谱系的特定获取。为了解决这些假设，我们的建议受到了指导 通过三个具体的目的：1)论证TGFb/Smad2-Smad3信号的需求和贡献 在NC形成的早期阶段，2)确定WNT和/或TGFb的新的候选效应并表征 它们对获得NC命运的具体贡献，以及3)评估它们在脊椎动物体内的功能 胚胎。这一创新方案利用了一个健壮的人类NC形成模型 多能干细胞和经典鸡胚胎学，首次解决了可能的贡献 TGFb信令(而不是BMP)，并追求一种综合的方法来解决 WNT和TGFb的组合信号转导。这项提议意义重大，因为这一领域的收益将 对FATE获取和分化的关键方面的影响适用于其他类型的细胞，并应改善我们的 管理与NC相关的许多病症的能力。