Genetic Regulation of Developmental and Regenerative Growth

项目摘要/摘要 我们研究的总体目标是了解调节增长的机制：在 单个细胞，在器官和生物体水平上。为了研究生长发育的规律，我们 研究了果蝇的想象盘，果蝇是成虫结构的前体，如翅膀。 直到最近，我们工作的一个重要限制是我们几乎没有研究细胞异质性的工具 这是体内生长调节的一个关键特征。单细胞转录组技术使我们能够将小分子 对生长调节有重大影响的细胞亚群。通过将此方法与实验相结合 遗传学，我们现在可以研究生长调控的一个关键方面，涉及异型相互作用 细胞的一小部分。 我们的目标是更好地了解再生生长的遗传调控。我们已经确定了一个 基因调控网络对于正常发育是完全不必要的，但对于再生是必不可少的 成长。从我们的单细胞研究中发现的其他基因指向特定表达在 再生胚泡的不同部分，可能调节再生的不同方面 包括增殖、细胞形态和细胞命运可塑性。我们将描述这些基因的功能。我们 他们还发现，椎间盘一部分的损伤和再生会影响椎间盘的发育 盘的其余部分和远处的器官。另一个目标是阐明这些长期的- 射程现象。 我们将研究离子通道在调节Hedgehog信号中的作用以及Hedgehog信号的生长和模式 机翼圆盘的。我们将确定去极化程度更高的细胞存活的原因。 优选地位于翼盘的前室。我们还将研究 生长调节中的机械敏感通道Piezo。 最后，通过将我们的翼盘单细胞图谱与基因筛查相结合，我们已经识别了许多 编码特性不佳的细胞表面蛋白和配体-受体对的基因可能在 调节细胞存活、细胞增殖和平面细胞极性的研究进展。我们将研究这些基因。

PROJECT SUMMARY/ABSTRACT The overall goal of our research is to understand the mechanisms that regulate growth: at the level of the individual cell, at the level of organs and at an organismal level. In order to study the regulation of growth, we have studied the imaginal discs of Drosophila, the larval precursors of adult structures such as the wing. Until recently, an important limitation to our work was that we had few tools to study the cellular heterogeneity that is a key feature of growth regulation in vivo. Single-cell transcriptomics allows us to characterize small subsets of cells that have a major impact on growth regulation. By combining this approach with experimental genetics, we can now study a key aspects of growth regulation that involves heterotypic interactions between small subsets of cells. We aim to obtain a better understanding of the genetic regulation of regenerative growth. We have identified a gene regulatory network that is entirely dispensable for normal development but is essential for regenerative growth. Additional genes identified from our single-cell studies point to genes that are specifically expressed in different portions of the regeneration blastema and which likely regulate different aspects of regeneration including proliferation, cell shape and cell-fate plasticity. We will characterize the function of these genes. We have also found that damage and regeneration of one portion of the disc can impact the development of the remainder of the disc and also distant organs. Another goal is to elucidate the mechanistic basis of these long- range phenomena. We will examine the role of ion channels in regulating Hedgehog signaling and the growth and patterning of the of the wing disc. We will determine why cells with a more depolarized membrane potential survive preferentially in the anterior compartment of the wing disc. We will also study the properties of the mechanosensitive channel Piezo in growth regulation. Finally, by combining our single cell atlas of the wing disc with a genetic screen, we have identified many genes encoding poorly-characterized cell-surface proteins and ligand-receptor pairs that likely function during development to regulate cell survival, cell proliferation and planar cell polarity. We will study these genes.