Regulation of embryonic epithelial morphogenesis

胚胎上皮形态发生的调节

基本信息

批准号：
8135984
负责人：
Shaohua Li
金额：
$ 30.58万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8135984
关键词：
1-Phosphatidylinositol 3-Kinase Adhesions Affect Apical Apoptosis Architecture Basement membrane Binding Biochemical Genetics Biological Models Biology Cancer Biology Cell Polarity Cell Survival Cell membrane Cells Complex Cues DNA DOCK1 protein Data Defect Development Dominant-Negative Mutation Embryo Embryonic Development Environment Epiblast Epithelial Epithelial cyst Epithelium Event Exhibits Exocytosis Experimental Models GTP Binding Genes Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate IQ motif containing GTPase activating protein 1 In Situ Nick-End Labeling In Vitro Inner Cell Mass Integrins Lead Maintenance Malignant - descriptor Mediating Methods Microtubules Molecular Morphogenesis Mus Natural regeneration Pathway interactions Phenotype Play Process Proteins Recruitment Activity Regulation Retroviridae Role Signal Transduction Staging Staining method Stains Testing Time Tissue Engineering Tissues Undifferentiated Work Wound Healing blastocyst caspase-3 embryonic stem cell extracellular genetic manipulation implantation integrin-linked kinase knock-down mutant natural Blastocyst Implantation novel protein complex protein transport public health relevance rho GTP-Binding Proteins small hairpin RNA tissue regeneration tool trafficking

项目摘要

DESCRIPTION (provided by applicant): Formation of polarized epithelium is fundamental to embryonic development. During mouse peri- implantation development, the undifferentiated inner cell mass of the blastocyst is converted from a nonpolar cell aggregate to a highly organized epithelial cyst. This morphogenetic transformation involves the polarization and basement membrane (BM)-dependent survival of epiblast epithelium. However, the molecular mechanisms underlying these processes are largely unknown. The mouse peri-implantation development can be recapitulated by in vitro cultured embryoid bodies (EBs) differentiated from embryonic stem cells. Using genetically modified EBs, we show for the first time that BM formation directs the assembly of an adhesion complex, which serves as a signaling platform to regulate epiblast polarization and survival. Our preliminary data supporting this idea, demonstrating that (1) assembly of the BM-associated adhesion complexes correlates with the activation of Rho GTPases Cdc42 and Rac1; (2) Cdc42 controls microtubule organization and the trafficking of apical polarity proteins, processes that are required for cell elongation and polarization; and (3) Rac1 activation plays an essential role in BM-dependent epiblast survival. These data strongly support our hypothesis that BM formation induces epiblast polarization and promotes epiblast survival via activation of Cdc42 and Rac1. To test this hypothesis, we propose to determine the mechanism through which the assembly of BM-associated adhesion complexes induces Cdc42 and Rac1 activation (Specific Aim 1 and 3). Next, we will determine the Cdc42-effector interactions that regulate epiblast elongation and apical polarization, focusing on the role of IQGAP1 in microtubule capture and the exocyst in apical polarity protein trafficking (Specific Aim 2). Finally, we will determine the Rac1- effector interactions that regulate epiblast survival (Specific Aim 4). The long-term goal of this study is to identify the extracellular cues and the transmembrane cascades that regulate embryonic epithelial morphogenesis, which are crucial to our understanding of epithelial biology, embryogenesis, and tissue regeneration. Public Health Relevance: Elucidating the molecular mechanisms of embryonic epithelial tissue formation that integrate cellular polarity, differentiation and survival with tissue architecture is not only critical to our understanding of embryonic development and cancer biology but also has implications in tissue regeneration and tissue engineering.

描述（由申请人提供）：极化上皮的形成是胚胎发育的基础。在小鼠植入周围发育过程中，囊胚的未分化内细胞团从非极性细胞聚集体转变为高度组织化的上皮囊肿。这种形态发生转变涉及外胚层上皮的极化和基底膜（BM）依赖性存活。然而，这些过程背后的分子机制很大程度上是未知的。小鼠的植入周围发育可以通过体外培养的胚胎干细胞分化的胚状体（EB）来重现。使用转基因 EB，我们首次证明 BM 形成指导粘附复合物的组装，该粘附复合物充当调节外胚层极化和存活的信号平台。我们的初步数据支持这一想法，表明 (1) BM 相关粘附复合物的组装与 Rho GTPases Cdc42 和 Rac1 的激活相关； (2) Cdc42 控制微管组织和顶端极性蛋白的运输，这是细胞伸长和极化所需的过程； (3) Rac1 激活在 BM 依赖性外胚层存活中发挥重要作用。这些数据有力地支持了我们的假设，即 BM 形成诱导外胚层极化并通过 Cdc42 和 Rac1 的激活促进外胚层存活。为了检验这一假设，我们建议确定 BM 相关粘附复合物的组装诱导 Cdc42 和 Rac1 激活的机制（具体目标 1 和 3）。接下来，我们将确定调节外胚层伸长和顶端极化的 Cdc42 效应子相互作用，重点关注 IQGAP1 在微管捕获中的作用和外囊在顶端极性蛋白运输中的作用（具体目标 2）。最后，我们将确定调节外胚层存活的 Rac1 效应子相互作用（具体目标 4）。这项研究的长期目标是确定调节胚胎上皮形态发生的细胞外信号和跨膜级联，这对于我们理解上皮生物学、胚胎发生和组织再生至关重要。公共健康相关性：阐明胚胎上皮组织形成的分子机制，将细胞极性、分化和存活与组织结构结合起来，不仅对我们理解胚胎发育和癌症生物学至关重要，而且对组织再生和组织工程也具有重要意义。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cdc42 controls vascular network assembly through protein kinase Cι during embryonic vasculogenesis.

Cdc42 在胚胎血管发生过程中通过蛋白激酶 Cδ 控制血管网络组装。

DOI：
发表时间：
2011-08
期刊：
影响因子：
0
作者：
Qi, Yanmei;Liu, Jie;Wu, Xunwei;Brakebusch, Cord;Leitges, Michael;Han, Yaling;Corbett, Siobhan A;Lowry, Stephen F;Graham, Alan M;Li, Shaohua
通讯作者：
Li, Shaohua

Integrins are required for the differentiation of visceral endoderm.

内脏内胚层的分化需要整合素。

DOI：
发表时间：
2009-01-15
期刊：
影响因子：
4
作者：
Liu, Jie;He, Xiaowen;Corbett, Siobhan A;Lowry, Stephen F;Graham, Alan M;Fässler, Reinhard;Li, Shaohua
通讯作者：
Li, Shaohua

PTEN induces apoptosis and cavitation via HIF-2-dependent Bnip3 upregulation during epithelial lumen formation.

PTEN 在上皮腔形成过程中通过 HIF-2 依赖性 Bnip3 上调诱导细胞凋亡和空化。

DOI：
发表时间：
2015-05
期刊：
影响因子：
12.4
作者：
Qi, Y;Liu, J;Saadat, S;Tian, X;Han, Y;Fong, G;Pandolfi, P P;Lee, L Y;Li, S
通讯作者：
Li, S

Talin1 regulates integrin turnover to promote embryonic epithelial morphogenesis.

Talin1 调节整合素周转以促进胚胎上皮形态发生。

DOI：
发表时间：
2011-08
期刊：
影响因子：
5.3
作者：
Liu, Jie;He, Xiaowen;Qi, Yanmei;Tian, Xiaoxiang;Monkley, Susan J;Critchley, David R;Corbett, Siobhan A;Lowry, Stephen F;Graham, Alan M;Li, Shaohua
通讯作者：
Li, Shaohua

Bnip3 and AIF cooperate to induce apoptosis and cavitation during epithelial morphogenesis.

Bnip3 和 AIF 在上皮形态发生过程中协同诱导细胞凋亡和空化。

DOI：
发表时间：
2012-07-09
期刊：
影响因子：
0
作者：
Qi, Yanmei;Tian, Xiaoxiang;Liu, Jie;Han, Yaling;Graham, Alan M;Simon, M Celeste;Penninger, Josef M;Carmeliet, Peter;Li, Shaohua
通讯作者：
Li, Shaohua