REGULATION OF NODAL SIGNALING IN HOLOPROSENCEPHALY

前脑无裂畸形中节点信号传导的调节

• 批准号: 6819882
• 负责人: Jixiang Ding
• 金额: $ 32.61万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6819882
• 关键词: biological signal transduction; brain morphology; cleft lip; congenital brain disorder; congenital oral /facial /cranial defect; developmental genetics; developmental neurobiology; embryogenesis; epidermal growth factor; gene targeting; genetic manipulation; genetic models; genetically modified animals; growth factor receptors; homeobox genes; laboratory mouse; mammalian embryology; microarray technology; molecular biology; neurogenesis; phenotype; protein structure function; transforming growth factors

DESCRIPTION (provided by applicant): Holoprosencephaly represents a common birth defect (1:16,000 in live births and 1:250 in stillbirths) with a broad spectrum of craniofacial malformations ranging from distressful cyclopia to mild symptom of a single central incisor. It is caused by defects in the specification of the ventral forebrain (a part of the anterior axial midline), which subsequently lead to incomplete separation of the brain into the left and right hemispheres. Recent studies indicated that Nodal signaling plays a central role in controlling midline development, we therefore will focus on the regulation of Nodal signaling in mouse embryogenesis with a special interest in anterior axial midline formation. Nodal is a member of the transforming growth factor beta (TGF-beta) superfamily that utilizes a signaling pathway defined by Activin type I and II receptors, Smad2 and 4, and FoxH1 (FAST). Importantly, members of the EGF-CFC family of extracellular proteins such as mouse Cripto are essential co-factors for Nodal. We previously reported a Cripto Null allele, and recently we generated a Cripto hypomorphic allele, Cripto3-loxP, by genetic manipulation. Approximately 50 percent of the Cripto3-loxP/CriptoNull mice displayed a wide range of axial midline defects resembling holoprosencephaly. In contrast, TGIF is a homeobox gene encoding a nuclear protein that antagonizes TGF-( signaling by blocking Smad2 function. Interestingly, mutations in human TGIF gene are associated with holoprosencephaly, suggesting its function in axial midline formation, presumably through regulating Nodal/Smad2 signaling pathway. Based on these results, we will pursue the following Specific Aims in the proposed research: I) Analysis of the Cripto3-loxP/CriptoNull mice as a model system for ventral forebrain defects and HPE by detailed analysis of the defects in Cripto3-loxP/CriptoNull mice at morphology and molecular levels; II) Investigation of mechanisms underlying Cripto function in mouse axial midline formation by identifying the tissues and cells where Cripto is functioning and downstream target genes of Cripto; III) Investigation of TGIF function in mouse axial midline development by generating TGIF null embryos and examining the modulation of Nodal signaling by TGIF. These studies should improve our understanding of mammalian axial midline formation and human holoprosencephaly.

描述（由申请人提供）：全脑畸形代表着一种常见的先天缺陷（现场出生中的1：16,000，在死产中1：250）具有广泛的颅面畸形，范围从苦恼的环岛到轻度的单个中央切牙。它是由腹前脑（前轴向中线的一部分）的缺陷引起的，该缺陷随后导致大脑不完全分离到左和右半球。最近的研究表明，节点信号在控制中线发育中起着核心作用，因此我们将重点介绍小鼠胚胎发生中淋巴结信号传导，对前轴向中线形成特别感兴趣。 Nodal是转化生长因子β（TGF-BETA）超级家族的成员，它利用了由激活素I型和II受体SMAD2和4和FOXH1（快速）定义的信号传导途径。重要的是，EGF-CFC家族的细胞外蛋白（如小鼠cripto）的成员是淋巴结的必不可少的辅助因素。我们以前报道了Cripto Null等位基因，最近我们通过基因操作产生了Cripto肌张力cripto3-loxp。大约50％的Cripto3-loxp/Criptonull小鼠显示出类似于全脑脑的各种轴向中线缺陷。 In contrast, TGIF is a homeobox gene encoding a nuclear protein that antagonizes TGF-( signaling by blocking Smad2 function. Interestingly, mutations in human TGIF gene are associated with holoprosencephaly, suggesting its function in axial midline formation, presumably through regulating Nodal/Smad2 signaling pathway. Based on these results, we will pursue the following Specific Aims in the proposed research: I) Analysis of the Cripto3-loxp/criptonull小鼠作为腹前脑缺陷和HPE的模型系统，通过详细分析cripto3-loxp/criptonull小鼠在形态和分子水平上的缺陷； ii）研究通过鉴定Cripto发挥功能和下游靶基因的组织和细胞来研究小鼠轴向中线形成中的机制； iii）通过产生TGIF无效胚胎并检查TGIF对淋巴结信号传导的调节，研究了小鼠轴向中线发育中TGIF功能。这些研究应提高我们对哺乳动物轴向中线形成和人类全脑的理解。