Molecular basis of digestive system development in Xenopus

爪蟾消化系统发育的分子基础

• 批准号: 9232138
• 负责人: Aaron M Zorn
• 金额: $ 33.95万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232138
• 关键词: Address; Animal Model; Binding; Cells; Complex; Congenital Abnormality; DNA; DNA Binding; Data; Deposition; Development; Digestive System Disorders; Disease; Disease model; Elements; Embryo; Embryonic Development; Endoderm; Environment; Extracellular Matrix; Feedback; Felis catus; Fibronectins; Gastrula; Genetic; Genetic Epistasis; Genetic Transcription; Goals; Grant; Growth Factor; Health; Hindgut; Homeobox Genes; Human; In Vitro; Intestines; Liver; Mammals; Maps; Mediating; Mesoderm; Metalloproteases; Modeling; Molecular; Morphogenesis; Nuclear; Organ; Organogenesis; Outcome; Output; Paper; Pathway interactions; Pattern; Peptide Hydrolases; Primitive foregut structure; Proteins; Publishing; Regulation; Regulatory Element; Replacement Therapy; Research; Role; Series; Signal Transduction; Specific qualifier value; Specificity; Stem cells; Systems Development; Testing; Time; Tissues; WNT Signaling Pathway; Xenopus; beta catenin; combinatorial; extracellular; gastrointestinal system; gastrulation; heparin proteoglycan; human stem cells; malformation; novel; progenitor; promoter; public health relevance; response; segregation; stem cell differentiation; syndecan-4

DESCRIPTION (provided by applicant): The long-term goal of this project is to elucidate the molecular mechanisms controlling embryonic development of the digestive system. This will have a broad and significant impact on our understanding of human GI malformations, inform strategies to direct the differentiation of stem cells and provide new fundamental information on cell signaling in development and disease. Digestive system development is regulated by a series of growth factor signals between the endoderm and mesoderm, which are only partially understood. The fundamental mechanism of GI development are highly conserved between mammals and other vertebrate species and our previous studies using the experimental advantages of Xenopus embryos has helped inform strategies to induce human intestinal tissue from stem cells. Despite recent advances, fundamental gaps in our understanding of how foregut and hindgut progenitors are specified remain. In particular how the extracellular environment regulates combinatorial signaling dynamics at different stages of GI development, and how transcriptional specificity in response to these signal is achieved are largely unknown and the focus of this proposal. Our preliminary studies support the hypothesis that Secreted Frizzed Related Proteins (Sfrp) regulate the extracellular Fibronectin matrix to promote BMP signaling by a novel mechanism, and that Sfrps coordinate signaling crosstalk between BMP and Wnt growth factors to pattern the endoderm into foregut and hindgut progenitors. Aim 1 will characterize the novel mechanisms by which Sfrps and Tolloid proteases modulate the Fibronectin matrix to regulate BMP signaling. Aim 2 will determine the mechanisms that coordinate BMP and Wnt signaling. Aim 3 will determine how differential activity of the BMP and Wnt signaling effectors Smad1 and beta-catenin are integrated on DNA cis-regulatory elements to control foregut versus hindgut transcription.

描述（由申请人提供）：该项目的长期目标是阐明控制消化系统胚胎发育的分子机制。这将对我们对人类胃肠道畸形的理解产生广泛而重大的影响，为指导干细胞分化的策略提供信息，并提供有关发育和疾病中细胞信号传导的新的基本信息。消化系统的发育是由内胚层和中胚层之间的一系列生长因子信号调节的，目前人们对这些信号的了解还只是部分。胃肠道发育的基本机制在哺乳动物和其他脊椎动物物种之间高度保守，我们之前利用非洲爪蟾胚胎的实验优势进行的研究有助于为从干细胞诱导人类肠道组织的策略提供信息。尽管最近取得了进展，但我们对前肠和后肠祖细胞如何指定的理解仍然存在根本差距。特别是细胞外环境如何在胃肠道发育的不同阶段调节组合信号动力学，以及如何实现响应这些信号的转录特异性在很大程度上是未知的，也是本提案的重点。我们的初步研究支持以下假设：分泌性卷曲相关蛋白 (Sfrp) 通过一种新机制调节细胞外纤连蛋白基质以促进 BMP 信号传导，并且 Sfrp 协调 BMP 和 Wnt 生长因子之间的信号串扰，从而将内胚层形成前肠和后肠祖细胞。目标 1 将描述 Sfrps 和 Tolloid 蛋白酶调节纤连蛋白基质以调节 BMP 信号传导的新机制。目标 2 将确定协调 BMP 和 Wnt 信号传导的机制。目标 3 将确定 BMP 和 Wnt 信号传导效应器 Smad1 和 β-连环蛋白的差异活性如何整合到 DNA 顺式调控元件上以控制前肠与后肠转录。

项目成果

Modeling human development and disease in Xenopus. Preface.

在非洲爪蟾中模拟人类发育和疾病。

• DOI: 10.1016/j.ydbio.2015.11.019
• 发表时间: 2015
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: LaBonne,Carole;Zorn,AaronM
• 通讯作者: Zorn,AaronM

A Retinoic Acid-Hedgehog Cascade Coordinates Mesoderm-Inducing Signals and Endoderm Competence during Lung Specification.

• DOI: 10.1016/j.celrep.2016.05.060
• 发表时间: 2016-06-28
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Rankin SA;Han L;McCracken KW;Kenny AP;Anglin CT;Grigg EA;Crawford CM;Wells JM;Shannon JM;Zorn AM
• 通讯作者: Zorn AM

Syndecan4 coordinates Wnt/JNK and BMP signaling to regulate foregut progenitor development.

Syndecan4 协调 Wnt/JNK 和 BMP 信号传导以调节前肠祖细胞发育。

• DOI: 10.1016/j.ydbio.2016.05.025
• 发表时间: 2016
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: Zhang,Zheng;Rankin,ScottA;Zorn,AaronM
• 通讯作者: Zorn,AaronM

Different thresholds of Wnt-Frizzled 7 signaling coordinate proliferation, morphogenesis and fate of endoderm progenitor cells.

Wnt-Frizz的不同阈值7信号传导坐标坐标增殖，形态发生和内胚层祖细胞的命运。

• DOI: 10.1016/j.ydbio.2013.02.024
• 发表时间: 2013-06-01
• 期刊: DEVELOPMENTAL BIOLOGY
• 影响因子: 2.7
• 作者: Zhang, Zheng;Rankin, Scott A.;Zorn, Aaron M.
• 通讯作者: Zorn, Aaron M.

Members of the DAN family are BMP antagonists that form highly stable noncovalent dimers.

• DOI: 10.1016/j.jmb.2012.10.003
• 发表时间: 2012-12-14
• 期刊: JOURNAL OF MOLECULAR BIOLOGY
• 影响因子: 5.6
• 作者: Kattamuri, Chandramohan;Luedeke, David M.;Nolan, Kristof;Rankin, Scott A.;Greis, Kenneth D.;Zorn, Aaron M.;Thompson, Thomas B.
• 通讯作者: Thompson, Thomas B.