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

生物学中的一个基本问题是细胞间的通信和来自局部组织微环境的短程信号的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的子细胞与局部组织微环境的适当通信。果蝇睾丸提供了一个很好的系统来研究在体内如何紧密并列的细胞类型相互沟通，以协调它们的共分化，因为体细胞囊肿干细胞和它们的子代体细胞囊肿细胞（统称为囊肿细胞）封装生殖细胞，创造一个囊肿微环境。到目前为止，这仍然是一个谜，这些紧密包装的囊肿如何协调皮质极性和细胞形状的变化与膜添加，细胞运输和信号在其接触部位，并没有机制描述果蝇睾丸中的囊肿细胞如何生长，伸长和包裹生殖细胞在不同的分化阶段。我的新的初步数据表明，囊肿细胞是至关重要的体细胞-种系囊肿的完整性和功能囊肿微环境是一个先决条件，囊肿细胞-种系协调的信号交换和共分化。这种密切相互作用的主要候选者是Dlg，Scrib和Lgl，高度保守的极性和支架蛋白，定位在睾丸囊肿细胞的皮质侧并控制睾丸囊肿的完整性。接下来的挑战是：（1）阐明囊细胞极性和结构，（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在囊细胞功能和囊细胞-种系协调中的作用，以及（3）研究Dlg如何以及在何种程度上与Lgl和Scrib协作以促进囊细胞极性和功能。Dlg、Scrib和Lgl功能的系统分析不仅将阐明胞囊细胞结构，而且最重要的是将鉴定参与局部胞囊细胞-生殖系通讯的关键基因产物和机制。使用成熟的遗传工具，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控制的方式操纵细胞功能，以解码信号传递，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-生殖细胞通讯的机制和因素将揭示其他组织和干细胞系统相关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能力的能力。

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.