Mechanisms of Cell Communication in Animal Development

摘要 我研究的主要目标是回答细胞和发育生物学中的一个主要问题：如何 细胞传递形态发生信号，在动物体内创造组织模式。在发展领域内 细胞可以精确地调节信号交换的水平、时间和位置。此控制中的任何异常 机制导致发育畸形和疾病。大多数现有的模型都提出了信令 蛋白质在细胞外空间扩散，产生浓度梯度，这些细胞外空间 梯度调节靶细胞的生长、迁移和构图。然而，我研究的一个主要焦点是 程序是为了理解一种截然不同的机制--由专门的肌动蛋白直接传递信号-- 富含信号的丝状孢子，称为细胞线。我之前的工作探索并首先确立了功能角色 在果蝇身上发现了这种新的机制。我的研究表明，细胞使用细胞素直接交换信号 细胞素介导的信号传递对于细胞间的交流是必不可少的。我最近的工作主要集中在 后生动物发育过程中的关键信号蛋白成纤维细胞生长因子及其在细胞中的分布 通过细胞素传递到细胞。我们证明了成纤维细胞生长因子作为一种形态因子，引起浓度依赖。 在气管发育过程中的反应，即成纤维细胞生长因子的梯度是由蛋白酶依赖的切割控制的 而且成纤维细胞生长因子的梯度是由细胞素介导的信号转导形成的。最近，我们也有 揭示了成纤维细胞生长因子复杂的翻译后处理，可能控制其接触依赖的交换。我的 目前的研究正在利用强大的最先进的显微成像、生物化学、细胞 生物学和果蝇遗传学继续探索和研究控制细胞线的机制 中介信号交换和信号分散。考虑到在所有 对于动物，我们的研究将对人类的发育和疾病知识产生持久的影响。

SUMMARY The broad objective of my research is to answer a major question in cell and developmental biology: how do cells communicate morphogenetic signals to create tissue patterns in animals. Within a developmental field cells can precisely regulate the levels, timing and location of signal exchange. Any aberration in this control mechanism leads to developmental malformations and disease. Most existing models propose that signaling proteins diffuse in the extracellular space to generate concentration gradients, and that these extracellular gradients regulate growth, migration and patterning of target cells. However, a major focus of my research program is to understand a radically different mechanism - the ‘direct delivery’ of signals by specialized actin- rich signaling filopodia, named cytonemes. My previous work explored and first established the functional role of this novel mechanism in Drosophila. My work showed that cells use cytonemes to directly exchange signals and that cytoneme-mediated signaling is essential for cell-cell communication. My recent work is focused on Fibroblast Growth Factor (FGF), a key signaling protein in metazoan development, and its dispersion from cell to cell by cytonemes. We demonstrated that FGF acts as a morphogen that elicits concentration-dependent responses during tracheal development, that the FGF gradient is controlled by protease-dependent cleavage of the molecule, and that the FGF gradient is formed by cytoneme-mediated signaling. Recently, we also have uncovered a complex post-translation processing of FGF that may control its contact-dependent exchange. My current research is taking advantage of powerful state-of-the art microscopic imaging, biochemistry, cell biology and Drosophila genetics to continue to explore and investigate the mechanisms that control cytoneme mediated signal exchange and signal dispersion. Given the conservation of signaling mechanisms in all animals, our research will have a lasting impact on knowledge about development and disease in humans.