The influence of tissue organization on the generation of TGF-ß signals and the function of stem cell niches in the Drosophila melanogaster germline.

本研究的目的是阐明组织如何通过控制细胞间信号的传播来形成干细胞壁龛。先前在几个系统中的工作表明，生态位和干细胞之间的粘附和信号传导过程在功能上是联系在一起的，并且已经提出，生态位信号的紧密空间调节是通过假定的基于粘附的“干细胞生态位突触”实现的，但其机制尚未得到很好的定义。我们将重点关注果蝇生殖系，其中BMP型TGF-β生长因子Dpp的信号传导有助于维持生殖系干细胞（GSC）池的生态位微环境。在雄性中，Dpp信号被严格限制在与Dpp源直接接触的生殖细胞中。由于在其他情况下，Dpp可以在许多细胞直径上发出信号，类似突触的机制可能限制BMP在壁龛- gsc界面上的扩散。我们最近开发了基于gfp的BMP受体激活活报告器，首次允许在亚细胞分辨率下检测活的BMP受体群体。正如干细胞突触假说所预测的那样，我们可以证明，在果蝇睾丸中，信号传导仅限于GSCs与BMP分泌小生境细胞接触的小块区域。因此，在这个项目中，我们将使用苍蝇遗传学和细胞生物学方法来干扰生态位组织组织，并从功能上解剖这种信号突触。

The aim of the proposed study is to elucidate how tissue organization shapes stem cell niches by controlling the spreading of intercellular signals. Previous work in several systems has suggested that adhesion and signaling processes between niche and stem cells are functionally linked, and it has been proposed that the tight spatial regulation of niche signaling is achieved via a putative adhesion based “stem cell niche synapse” that however is mechanistically not well defined. We will focus on the Drosophila germ line, where signalling by the BMP type TGF-β growth factor Dpp contributes to the niche microenvironment that maintains the germline stem cell (GSC) pool. In the male the Dpp signal is tightly limited to those germline cells in direct contact with the Dpp source. Since Dpp can signal over many cell diameters in other contexts a synapse like mechanism may confine BMP spreading at the niche-GSC interface. We have recently developed GFP-based live reporters for BMP receptor activation that for the first time allow detection of the active BMP receptor population live and at subcellular resolution. As predicted by the stem cell synapse hypothesis we could show that in the fly testis signalling is confined to small patches where the GSCs contact the BMP secreting niche cells. In this project we will therefore use fly genetics and cell biological methods to perturb niche tissue organisation and functionally dissect this signalling synapse.