Soma-Germline communication and coordination in Drosophila spermatogenesis: understanding the role of cortical polarity proteins Dlg, Lgl and Scrib in testis homeostasis

果蝇精子发生中的体细胞-种系通讯和协调：了解皮质极性蛋白 Dlg、Lgl 和 Scrib 在睾丸稳态中的作用

• 批准号: 290468141
• 负责人: Dr. Fani Papagiannouli
• 金额: --
• 依托单位: Medway School of Pharmacy
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290468141?language=en
• 关键词: Soma; Germline; communication; coordination; Drosophila

A fundamental question in biology is how cell-cell communication and exchange of short-range signals from the local tissue microenvironment regulates cell proliferation and cell fate for setting up functional tissues. In all adult tissues harboring stem cells, tissue homeostasis and repair relies on the proper communication of stem cells and of their differentiating daughter cells with the local tissue microenvironment. The Drosophila testis provides an excellent system to study in vivo how closely apposed cell types reciprocally communicate to coordinate their co-differentiation, since the somatic cyst stem cells and their daughter somatic cyst cells (collectively called cyst cells) encapsulate the germ cells creating a cyst microenvironment. So far, it remains a mystery how these tightly packed cysts coordinate cortical polarity and cell shape changes with membrane addition, cellular trafficking and signaling at their contact sites, and there is no mechanism describing how cyst cells in Drosophila testis grow, elongate and ensheath the germ cells in various stages of differentiation. My new preliminary data suggest that cyst cells are crucially important for soma-germline cyst integrity and a functional cyst microenvironment is a prerequisite for cyst cell-germline coordination in terms of signaling exchange and co-differentiation. Primary candidates for this intimate interaction are Dlg, Scrib and Lgl, highly conserved polarity and scaffolding proteins that localize at the cortical side of the testis cyst cells and control testicular cyst integrity. The immediate next challenges are to: (1) elucidate cyst cell polarity and architecture, (2) investigate the role of Dlg in cyst cell function and cyst cell-germline coordination, by characterizing the Dlg phenotype and protein dynamics, and by mapping the functional role of the Dlg protein domains, and (3) investigate how and to what extend Dlg collaborates with Lgl and Scrib to promote cyst cell polarity and function. Systematic analysis of Dlg, Scrib and Lgl function will elucidate not only cyst cell architecture, but most importantly will identify key gene products and mechanisms involved in local cyst cell-germline communication. Using well-established genetic tools, cell-type specific markers and high-resolution imaging techniques we can manipulate cell function in a spatio-temporal controlled way within the soma-germline microenvironment to decode how signal transmission, membrane trafficking, cell morphological changes and polarity are established, maintained and coordinated. Elucidating the mechanisms and factors that regulate polarity and soma-germline communication will uncover molecular paradigms for regulatory strategies relevant in other tissues and stem cell systems, and will eventually advance our ability to access the power of stem cells in therapeutic applications.

生物学中的一个基本问题是细胞间的通讯和来自局部组织微环境的短距离信号交换如何调节细胞增殖和细胞命运以建立功能组织。在所有含有干细胞的成体组织中，组织稳态和修复依赖于干细胞及其分化子细胞与局部组织微环境的适当交流。由于体细胞囊肿干细胞及其子代体细胞囊肿细胞（统称为囊肿细胞）包裹生殖细胞，形成囊肿微环境，果蝇睾丸提供了一个很好的系统来研究体内密切相关的细胞类型如何相互沟通以协调它们的共分化。到目前为止，这些紧密排列的包囊是如何随着膜的添加、细胞运输和接触部位的信号传导而协调皮质极性和细胞形状变化的，仍然是一个谜，也没有机制描述果蝇睾丸中的包囊细胞在不同分化阶段如何生长、伸长和包膜生殖细胞。我的新初步数据表明，囊肿细胞对体细胞-种系囊肿的完整性至关重要，而功能性的囊肿微环境是囊肿细胞-种系在信号交换和共分化方面协调的先决条件。这种密切相互作用的主要候选蛋白是Dlg、Scrib和Lgl，它们是高度保守的极性和支架蛋白，位于睾丸囊肿细胞的皮质侧，控制睾丸囊肿的完整性。接下来的挑战是：(1)阐明囊肿细胞的极性和结构，(2)通过表征Dlg表型和蛋白质动力学，并通过绘制Dlg蛋白结构域的功能作用，研究Dlg在囊肿细胞功能和囊肿细胞-种系协调中的作用，以及(3)研究Dlg如何以及在多大程度上与Lgl和Scrib合作促进囊肿细胞极性和功能。系统分析Dlg、Scrib和Lgl的功能不仅可以阐明囊肿细胞的结构，更重要的是可以确定参与局部囊肿细胞-种系通讯的关键基因产物和机制。利用成熟的遗传工具、细胞类型特异性标记和高分辨率成像技术，我们可以在体细胞-种系微环境中以时空可控的方式操纵细胞功能，解码信号传递、膜运输、细胞形态变化和极性是如何建立、维持和协调的。阐明调节极性和体细胞-种系通讯的机制和因素，将揭示与其他组织和干细胞系统相关的调节策略的分子范式，并最终提高我们在治疗应用中获得干细胞力量的能力。