The role of the Lin28 regulatory pathway in early development

Lin28 调控途径在早期发育中的作用

• 批准号: BB/H000925/1
• 负责人: Harry Isaacs
• 金额: $ 52.99万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH000925%2F1
• 关键词: role; Lin28; regulatory; pathway; early

Animal development begins with a single cell, the fertilized egg. This cell contains all the information necessary to generate the complex body of the adult organism, containing many diverse cell types such as muscle, blood, nerve cells etc. The various cells of the embryo all contain the same genetic information. However, not all of this genetic information is used in each cell-type. Each cell-type is characterized by a different pattern of gene activity which is necessary for them to fulfill their various functions within the body. As developmental biologists we are interested in understanding the mechanisms involved in generating these diverse patterns of gene activity. Work in recent decades has shown that the cells of the developing embryo communicate with each other via secreted proteins known as growth factors. Signals passing from cell to cell play a key role in directing which cell types will eventually be formed. During development such signals act to change cell fate by activating or inhibiting groups of genes within a responding cell. These genes act as internal switches directing development of a particular cell types. The fibroblast growth factors (FGFs) are a related group of signaling proteins which are present in all animals. Our laboratory is interested in understanding the role of the FGFs in regulating gene activity in early animal development. The animal of choice for these studies is the frog Xenopus. The embryos of this organism are ideally suited for these studies for a number of reasons. The embryos are large, can be obtained in large numbers and develop rapidly outside the mother. Furthermore, there are excellent techniques available for analyzing and manipulating gene activity in the developing Xenopus embryo. We have recently undertaken a study which has enabled us to identify many of the genes which are regulated by FGF signaling in the cells of the early embryo. One of the genes that we identified as being a target of FGF signaling is Lin28. Our preliminary experiments, which have led to this proposal, indicate that Lin28 has a critical role in early frog development. If we inhibit lin28 function the head-to-tail pattern of the embryo is severely disrupted. Interestingly our experiments suggest that part of Lin28 function is associated with modulating the response of embryonic cells to growth factor signaling. Recently there has been considerable interest in Lin28 because it appears to be important in regulating how stem cells behave in culture. We believe that investigating how Lin28 functions in early development will have great benefits in understanding Lin28 function in stem cells. We plan to investigate in detail the role of Lin28 in frog development and have designed experiments which will allow us to determine how Lin28 regulates growth factor signaling. Lin28 codes for a protein which binds to and regulates the activity of various RNA molecules in the cell. These RNAs fall into two broad classes 1) protein coding messenger RNAs and 2) regulatory microRNAs, which regulate the activity of other protein coding messenger RNAs. The identification of these targets will greatly increase our understanding of how Lin28 functions during early development. We plan to share our observations with our collaborators working on human stem cells in culture. This will eventually allow us to test whether conclusions made about Lin28 activities during early development also apply to stem cells in culture.

动物的发育始于一个细胞，即受精卵。这个细胞包含了生成成年生物体的复杂身体所需的所有信息，包含许多不同的细胞类型，如肌肉，血液，神经细胞等。然而，并非所有这些遗传信息都用于每种细胞类型。每种细胞类型的特征在于不同的基因活性模式，这是它们在体内履行各种功能所必需的。作为发育生物学家，我们有兴趣了解产生这些不同基因活性模式的机制。近几十年来的研究表明，发育中的胚胎细胞通过被称为生长因子的分泌蛋白相互交流。从细胞到细胞的信号传递在指导最终形成哪种细胞类型方面起着关键作用。在发育过程中，这些信号通过激活或抑制应答细胞内的基因组来改变细胞命运。这些基因充当内部开关，指导特定细胞类型的发育。成纤维细胞生长因子（FGF）是存在于所有动物中的一组相关的信号蛋白。我们的实验室有兴趣了解FGF在早期动物发育中调节基因活性的作用。这些研究选择的动物是蛙爪蟾。这种生物的胚胎非常适合这些研究，原因有很多。胚胎很大，可以大量获得，并在母体外迅速发育。此外，有很好的技术可用于分析和操纵非洲爪蟾胚胎发育中的基因活性。我们最近进行了一项研究，使我们能够确定许多基因，这些基因是由FGF信号在早期胚胎细胞中调节的。我们鉴定为FGF信号传导靶点的基因之一是Lin 28。我们的初步实验，这导致了这一建议，表明林28在早期青蛙的发展有一个关键作用。如果我们抑制lin 28的功能，胚胎的头-尾模式就会被严重破坏。有趣的是，我们的实验表明，Lin 28的部分功能与调节胚胎细胞对生长因子信号的反应有关。最近，人们对Lin 28产生了相当大的兴趣，因为它似乎在调节干细胞在培养中的行为方面很重要。我们相信，研究Lin 28在早期发育中的功能将对理解Lin 28在干细胞中的功能有很大的好处。我们计划详细研究Lin 28在青蛙发育中的作用，并设计了实验，使我们能够确定Lin 28如何调节生长因子信号。Lin 28编码一种蛋白质，该蛋白质结合并调节细胞中各种RNA分子的活性。这些RNA分为两大类：1）蛋白质编码信使RNA和2）调节性微RNA，其调节其他蛋白质编码信使RNA的活性。这些目标的确定将大大增加我们对Lin 28在早期发育过程中如何发挥作用的理解。我们计划与我们在培养人类干细胞方面的合作者分享我们的观察结果。这最终将使我们能够测试关于Lin 28在早期发育过程中的活动的结论是否也适用于培养中的干细胞。

项目成果

Human Lin28 Forms a High-Affinity 1:1 Complex with the 106~363 Cluster miRNA miR-363.

• DOI: 10.1021/acs.biochem.6b00682
• 发表时间: 2016-09-13
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Peters, Daniel T.;Fung, Herman K. H.;Levdikov, Vladimir M.;Irmscher, Tobias;Warrander, Fiona C.;Greive, Sandra J.;Kovalevskiy, Oleg;Isaacs, Harry V.;Coles, Mark;Antson, Alfred A.
• 通讯作者: Antson, Alfred A.