Signaling regulation during development

发育过程中的信号调节

• 批准号: 355715-2011
• 负责人: VanRaay, Terence
• 金额: $ 2.55万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=572641
• 关键词: Signaling; regulation; during; development

The generation of a multicellular organism is the result of exquisite control of numerous signalling pathways during development, which are turned on and off numerous times with precision to fine-tune the body plan. Signalling cascades have built in mechanisms to control the strength and duration of the signal and understanding these self-induced regulators is the long-term objective of my research plan. To investigate how these self-induced regulators affect signalling involved in embryonic patterning I will use the well-established zebrafish embryo as a model for development. To probe further into the signalling cascade requires investigation at the cellular and biochemical level, for which I will use human cell lines. To link these two areas of investigation, I will also use zebrafish as an in vivo cell model, to test for the conservation of mechanism. Using these tools, I will focus on the Wnt signalling pathway. The Wnt signalling pathway is one of a handful of signalling cascades that are required for proper patterning of the early embryo and is used throughout development. When Wnt signalling is induced in the embryo it results in the transcription of many genes, two of which are Naked Homolog 1 (Nkd1) and Axin2. As these genes turn Wnt signalling off, they are considered negative regulators. The objective of this proposal will be to determine how Nkd1 and Axin2 cooperate with, or differ from, Axin1 a core component of the Wnt signalling machinery. Axin1 is involved in keeping the Wnt signal off in the absence of a Wnt signal, but also keeping the signal on in the presence of Wnt signalling (a switch so to speak). Nkd1 interacts with Axin1 and so in Aim 1, I will determine if Nkd1 limits the positive function, or enhances the negative function, of Axin1. In Aim2 I will determine how the conserved domains in Nkd1 affect its function as a negative regulator and in Aim 3 I will determine how Axin2 functionally differs from Axin1. This work will advance our basic understanding of how signalling cascades regulate themselves to achieve a properly patterned embryo.

多细胞生物体的产生是在发育过程中对众多信号通路进行精密控制的结果，这些信号通路被精确地打开和关闭无数次，以微调身体计划。信号级联已经建立了控制信号强度和持续时间的机制，了解这些自我诱导的调节器是我研究计划的长期目标。 为了研究这些自我诱导的调节因子如何影响胚胎模式化中的信号传导，我将使用成熟的斑马鱼胚胎作为发育模型。 为了进一步探索信号级联需要在细胞和生物化学水平上进行研究，我将使用人类细胞系。 为了将这两个领域的研究联系起来，我还将使用斑马鱼作为体内细胞模型，来测试其保守性机制。 使用这些工具，我将专注于Wnt信号通路。 Wnt信号通路是早期胚胎正确模式化所需的少数信号级联之一，并在整个发育过程中使用。 当Wnt信号在胚胎中被诱导时，它导致许多基因的转录，其中两个是裸同源物1（Nkd 1）和Axin 2。当这些基因关闭Wnt信号时，它们被认为是负调控因子。 本提案的目的是确定Nkd 1和Axin 2如何与Wnt信号传导机制的核心组成部分Axin 1合作或不同。 Axin1参与在Wnt信号不存在的情况下保持Wnt信号关闭，但也在Wnt信号存在的情况下保持信号打开（可以说是开关）。Nkd 1与Axin 1相互作用，因此在目标1中，我将确定Nkd 1是否限制Axin 1的正功能或增强其负功能。 在目标2中，我将确定Nkd1中的保守结构域如何影响其作为负调节因子的功能，在目标3中，我将确定Axin2在功能上与Axin1有何不同。 这项工作将推进我们对信号级联如何自我调节以实现正确模式化胚胎的基本理解。