GENETIC BASIS OF MESENCEPHALIC/METENCEPHALIC PATTERNING

中脑/后脑模式的遗传基础

• 批准号: 6627704
• 负责人: Daniel S Kessler
• 金额: $ 34.75万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-18 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6627704
• 关键词: DNA binding protein; biological signal transduction; brain regulatory center; cell differentiation; chick embryo; developmental genetics; developmental neurobiology; fibroblast growth factor; gene expression; glycoproteins; mesencephalon; microinjections; morphometry; neuroanatomy; neurogenetics; neurophysiology; protein tyrosine kinase; protooncogene; rhombencephalon; serial analysis of gene expression; transcription factor; vertebrate embryology; zebrafish

DESCRIPTION (From the Applicant's Abstract): The long-term goal of this research is to understand the genetic basis of development in the mesencephalon (midbrain) and metencephalon (anterior hindbrain) region (MMR) of the brain. Pattern formation throughout the MMR is directed by the coordinated activity of the glycoproteins Wntl and Fgf8, which are secreted by cells within the isthmic organizer (IsO). The IsO is the key signaling center in MMR development yet the molecular mechanism of its action is poorly understood. Two of the most important questions are i) "how are the genes encoding Wntl and FGF8 regulated?" and ii) "what are their distinct roles in IsO patterning?" Fgf8 signaling in known to rely on the transcription factors Enl, En2, Pax2 and Pax5 and at least part of their function is to participate in an autoregulatory loop. Understanding whether they govern Wntl expression independent of Fgf8 is crucial but unknown. In contrast, our research identified a unique transcription factor, Lmxlb, as being a key regulator of Wntl, and suggested that neither Wntl nor Lmxlb are part of the proposed Fgf8/Pax/En autoregulatory pathway. Nevertheless, some form of interplay exists between these signaling pathways because Wntl and Fgf8 expression are codependent. We propose to perform genetic experiments using both chick and zebrafish model systems to dissect the mechanisms that govern Wntl and Fgf8 expression. Our specific aims are: 1. To determine whether Lmxlb/Wntl activity ever impinges on En/Pax/Fgf8 expression. 2. To determine whether Pax2 or Pax5 ever i) directly maintain the Lmxlb/Wntl pathway or ii) act as cofactors for Lmxlb maintenance of Wntl . 3. To determine whether Enl or En2 directly maintain the Lmxlb/Wntl pathway. These studies should allow us to construct a model describing the coordinate regulation of Wntl and Fgf8. This should give insight into how early mammalian development occurs and eventually suggest means of preventing or treating human birth defects.

描述（来自申请人的摘要）：本发明的长期目标是： 研究的目的是了解中脑发育的遗传基础 脑的中脑（midbrain）和后脑（metencephalon）（前后脑）区域（MMR）。 整个MMR的模式形成由以下协调活动指导： 由峡部内的细胞分泌的糖蛋白Wntl和Fgf 8 组织者（IsO）。IsO是MMR发展中的关键信号中心， 其作用的分子机制知之甚少。两个最 重要的问题是i）“编码Wntl和FGF 8的基因是如何 监管？它们在IsO模式中的独特作用是什么？“FGF8 已知信号传导依赖于转录因子En 1、En 2、Pax 2和Pax 5 至少它们的部分功能是参与一种自我调节 循环.了解它们是否独立于Fgf 8支配Wntl表达， 关键但未知相反，我们的研究发现了一种独特的 转录因子Lmxlb是Wntl的关键调节因子，并建议 Wntl和Lmxlb都不是提议的Fgf 8/Pax/En自动调节的一部分， 通路然而，这些信号之间存在某种形式的相互作用， 因为Wntl和Fgf 8表达是共依赖的。我们建议 使用小鸡和斑马鱼模型系统进行遗传实验， 剖析控制Wntl和Fgf 8表达的机制。我们的具体目标 是：1.为了确定Lmxlb/Wntl活性是否曾经影响En/Pax/Fgf 8 表情2.要确定Pax 2或Pax 5是否i）直接维护 Lmxlb/Wntl途径或ii）充当Wntl的Lmxlb维持的辅因子。3. 确定Enl或En 2是否直接维持Lmxlb/Wntl途径。这些 研究应该让我们建立一个模型， Wntl和Fgf 8的调节。这将有助于我们了解早期哺乳动物 并最终提出了预防或治疗人类疾病的方法。 出生缺陷