Genetic mechanisms of differentiation and morphogenesis

我的研究计划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(TJ)蛋白是果蝇性腺这些过程的关键调节因子，我们将其用作模型系统。TJ是哺乳动物中大的MAF转录因子的近亲，这些转录因子在细胞分化和癌症中起着多种作用。在果蝇的性腺中，生殖细胞在相邻体细胞的指导下发育，TJ在体细胞中发挥作用，控制它们的分化程序和相互之间以及与生殖细胞的适当相互作用的能力。在这里，我建议把重点放在两个依赖TJ的过程上，以进一步阐明它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中的干细胞由体细胞巢维持。我们发现TJ对于这个生态位的形成是必不可少的。在这里，我们建议识别和分析在TJ控制下控制不同体细胞生态位细胞发育和空间排列的因素。(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控制细胞在卵泡中的迁移，并确定蛋白激酶C增量(PKCδ)是TJ的一个潜在靶点。TJ和Pkcd似乎都调节细胞突起中的丝状肌动蛋白的结构。在这里，我们建议研究PKCδ在细胞迁移过程中调节肌动蛋白细胞骨架的功能以及它与其他肌动蛋白调节因子的相互作用。总而言之，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引导组织发育的Maf依赖过程有更全面的理解。

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 (Pkcδ) 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 Pkcδ 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.