Genetic mechanisms of differentiation and morphogenesis

分化和形态发生的遗传机制

• 批准号: RGPIN-2017-06780
• 负责人: Godt, Dorothea
• 金额: $ 2.48万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=712449
• 关键词: Genetic; mechanisms; differentiation; morphogenesis

The goal of my research program is to gain an understanding of molecular networks that drive cell differentiation and behaviour and define the shape and structure of tissues. The Traffic jam (Tj) protein is a key regulator of these processes in Drosophila gonads, which we use as a model system. Tj is a close relative of the large Maf transcription factors in mammals that have multiple roles in cell differentiation and cancer. In Drosophila gonads, where germ cells develop under the guidance of adjacent somatic cells, Tj functions in the somatic cells controlling their differentiation program and ability to properly interact with each other and with the germ cells. Here, I propose to focus on two Tj-dependent processes to further elucidate its function in regulating the morphogenetic behaviour of cells. (i) The stem cells in the gonads from which egg and sperm originate are sustained by a somatic niche. We discovered that Tj is essential for the formation of this niche. Here, we propose to identify and analyze the factors that control the development and spatial arrangement of the different somatic niche cells under the control of Tj. (ii) Cell migration plays an important role in normal development and cancer and is driven by actin-based cellular protrusions. We discovered that Tj controls cell migration in ovarian follicles and identified Protein kinase C delta (Pkc) as a potential target of Tj. Both Tj and Pkcd seem to regulate the structure of filamentous actin in cellular protrusions. Here, we propose to investigate the function of Pkc in regulating the actin cytoskeleton during cell migration and its interactions with other actin regulators. Collectively, this research will foster our understanding of the molecular network that operates downstream of the Maf transcription factor Tj and regulates the behaviour of cells contributing to cell migration and three-dimensional tissue organization. As Maf factors are conserved in mammals, I anticipate that our research will contribute to a more general understanding of Maf-dependent processes that guide tissue development.

我的研究项目的目标是了解驱动细胞分化和行为的分子网络，并定义组织的形状和结构。交通堵塞蛋白（Tj）是果蝇性腺中这些过程的关键调节器，我们将其作为模型系统。Tj是哺乳动物中大型Maf转录因子的近亲，在细胞分化和癌症中发挥多种作用。在果蝇性腺中，生殖细胞在相邻体细胞的引导下发育，Tj在体细胞控制其分化程序以及与生殖细胞相互作用的能力中起作用。在这里，我建议关注两个tj依赖的过程，以进一步阐明其在调节细胞形态发生行为中的功能。(i)产生卵子和精子的性腺干细胞由体细胞生态位维持。我们发现Tj对这个生态位的形成至关重要。在此，我们拟对Tj调控下不同体细胞生态位细胞发育和空间排列的控制因素进行识别和分析。（ii）细胞迁移在正常发育和癌症中发挥重要作用，并由基于肌动蛋白的细胞突起驱动。我们发现Tj控制卵巢卵泡中的细胞迁移，并确定蛋白激酶C δ (Pkc)是Tj的潜在靶点。Tj和Pkcd似乎都能调节细胞突起中丝状肌动蛋白的结构。在这里，我们建议研究Pkc在细胞迁移过程中调节肌动蛋白细胞骨架的功能及其与其他肌动蛋白调节因子的相互作用。总的来说，这项研究将促进我们对Maf转录因子Tj下游的分子网络的理解，并调节有助于细胞迁移和三维组织组织的细胞行为。由于Maf因子在哺乳动物中是保守的，我预计我们的研究将有助于对指导组织发育的Maf依赖过程有更广泛的了解。