Molecular Interactions during Neural Crest Formation

神经嵴形成过程中的分子相互作用

基本信息

批准号：
10660962
负责人：
MARTIN I. GARCIA-CASTRO
金额：
$ 48.89万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
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/10660962
关键词：
Address Amaze Animal Model Anterior Area Binding Birds CRISPR/Cas technology Candidate Disease Gene Cartilage Cell Lineage Cell model Cells Chick Chick Embryo Clustered Regularly Interspaced Short Palindromic Repeats Congenital Abnormality Development Dorsal Embryo Embryology Embryonic Development Emigrations Endothelin Endowment Epithelium 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 Pathway Signal Transduction Signaling Molecule Small Interfering RNA Stereotyping Testing Time Tretinoin Vertebrates WNT Signaling Pathway Work cell type combinatorial craniofacial bone experimental study gain of function human model improved in vivo innovation knock-down loss of function male melanocyte melanoma migration neural plate notch protein novel orofacial cleft programs rare condition receptor transcriptome sequencing vertebrate embryos

项目摘要

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rest细胞（NC）是脊椎动物独有的，在发育早期出现，从背面移民神经管，并分化为整个体内众多衍生物，促成神经元和神经胶质其他衍生物中的外周神经系统，黑素细胞和颅骨骨和软骨。失败的NC开发与大量称为神经疾病的疾病有关，包括常见的口腔裂，侵略性癌症和稀有综合症。这项研究的长期目标计划是为了促进我们对负责NC形成的最早信号事件的理解。当前由Wnt，FGF和BMP发出信号是确认对这一关键的一些关键输入之一 NC的形成，但是我们对执行其效果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，至关重要的是要确定这些途径调节的效应子并表征其效果。该提案的目标是：1）建立和表征第一次在NC组成之前，TGFB /SMAD2-SMAD3信号传导在分配之前进入神经管，迁移或分化； 2）确定Wnt和/或TGFB的效应子以及表征他们在NC早期形成中的作用。我们的假设是TGFB /SMAD2-SMAD3信号传导需要在NC组中发起最早的事件，以及TGFB和WNT响应的组合分子指导NC谱系的特定采集。为了解决这些假设，我们的提议得到了指导通过3个具体目的：1）证明TGFB /SMAD2-SMAD3信号的需求和贡献在NC组的早期方面，2）确定Wnt和/或TGFB的新型候选效应子并表征他们对NC命运的获取的具体贡献，以及3）评估其在体内功能胚胎。这项创新的建议利用了基于人类NC形成的强大模型多能干细胞和经典的雏鸡胚胎学首次解决了可能的贡献在此过程中，TGFB信令（不是BMP），并采用一种综合方法来解决 Wnt和TGFB的组合信号传导。该提议很重要，因为该领域的收益将有对适用于其他细胞类型的命运获取和分化的关键方面的影响，并应改善我们的管理与NC相关的许多病理的能力。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Current perspectives of the signaling pathways directing neural crest induction.

DOI：
10.1007/s00018-012-0991-8
发表时间：
2012-11
期刊：
CELLULAR AND MOLECULAR LIFE SCIENCES
影响因子：
8
作者：
Stuhlmiller, Timothy J.;Garcia-Castro, Martin I.
通讯作者：
Garcia-Castro, Martin I.

Top-Down Inhibition of BMP Signaling Enables Robust Induction of hPSCs Into Neural Crest in Fully Defined, Xeno-free Conditions.

DOI：
10.1016/j.stemcr.2017.08.008
发表时间：
2017-10-10
期刊：
Stem cell reports
影响因子：
5.9
作者：
Hackland JOS;Frith TJR;Thompson O;Marin Navarro A;Garcia-Castro MI;Unger C;Andrews PW
通讯作者：
Andrews PW

Distinct molecular profile and restricted stem cell potential defines the prospective human cranial neural crest from embryonic stem cell state.

DOI：
10.1016/j.scr.2020.102086
发表时间：
2020-12
期刊：
Stem cell research
影响因子：
1.2
作者：
Prasad MS;Charney RM;Patel LJ;García-Castro MI
通讯作者：
García-Castro MI

Analysis of early human neural crest development.

DOI：
10.1016/j.ydbio.2010.05.012
发表时间：
2010-08-15
期刊：
DEVELOPMENTAL BIOLOGY
影响因子：
2.7
作者：
Betters, Erin;Liu, Ying;Kjaeldgaard, Anders;Sundstrom, Erik;Garcia-Castro, Martin I.
通讯作者：
Garcia-Castro, Martin I.

Pax7 is regulated by cMyb during early neural crest development through a novel enhancer.

Pax7 在早期神经嵴发育过程中通过一种新型增强子受到 cMyb 的调节。

DOI：
10.1242/dev.088328
发表时间：
2013
期刊：
Development (Cambridge, England)
影响因子：
0
作者：
Vadasz,Stephanie;Marquez,Jonathan;Tulloch,Maria;Shylo,NataliaA;García-Castro,MartínI
通讯作者：
García-Castro,MartínI