The Drosophila foraging gene: gene regulation, pleiotropy and plasticity

遗传学家传统上研究与基因相关的单一明确功能。然而，许多基因在不同组织中具有多种功能（多效性），有时甚至在同一组织中。该提案从基因调控的角度研究了基因的不同部分如何支持不同的功能。我们假设觅食基因的模块化结构和复杂性促进了其多种功能。我们使用果蝇Drosophila melanogaster及其无与伦比的遗传工具包。我们的努力集中在果蝇觅食基因编码的信号分子称为cGMP依赖性蛋白激酶。觅食基因编码两种天然的等位基因变体，称为rover和sitter。在觅食时，漫游者比坐着的人移动得更多，找到的食物也更多。觅食基因有许多功能;除了觅食行为，它还调节学习和记忆，睡眠，压力反应和社会行为。在本研究中，我们从分子的角度探讨了觅食在果蝇社会行为中是如何实现其多效性功能的。 拟研究的社会行为有：1）幼虫社会觅食：幼虫社会觅食发生在高密度条件下，当3龄幼虫形成群体时，他们同步向下挖掘液化食物。在低密度饲养下，坐食者和流浪者都单独觅食（单独觅食），而在高密度饲养下，坐食者成群结队觅食（社会觅食），而流浪者（以及觅食基因基因缺失的幼虫）单独觅食。2)成年人的社会互动持续时间：在组中，成年坐蝇有显着更长的互动持续时间比漫游。社会隔离会减少坐者的互动持续时间，但不会减少漫游者的互动持续时间。遗传分析将许多成年人的社会表型与觅食基因联系起来。 觅食基因是一个由约35 kb DNA组成的复合基因。觅食基因产生许多基因产物，包括21个转录本和大约9个蛋白质异构体。 觅食基因在物种间是保守的，并在果蝇的整个发育和成年期的多个系统、组织和细胞中发现。在目前的提议中，我们的目标是研究1）觅食基因的复杂结构如何（多个启动子、RNA转录物和蛋白质异构体）在果蝇社会行为中起模块化作用，以及2）觅食基因及其表观遗传调节因子之间的相互作用如何调节社会行为（G9 a，组蛋白甲基转移酶基因，和microRNA，miR-932），以及社会环境（例如社会隔离）如何改变这些调控模式。这项研究将建立一个全面的和基础的理解，一个复杂的基因如何影响多种相互作用的表型，以产生正常的个体差异的社会行为。

Geneticists traditionally study a single well-defined function associated with a gene. However, many genes have multiple functions (pleiotropy) in different tissues and sometimes even within the same tissue. This proposal investigates how different parts of a gene support different functions, from a gene regulation perspective. We hypothesize that the foraging gene's modular structure and complexity facilitates its multiple functions. We use the fruit fly Drosophila melanogaster with its unsurpassed genetic tool kit. Our efforts are focused on the Drosophila foraging gene that encodes a signalling molecule called cGMP dependent protein kinase. The foraging gene encodes two natural allelic variants called rover and sitter. While foraging, rover flies move more and find more food than sitters. The foraging gene has many functions; in addition to foraging behaviour it modulates learning and memory, sleep, stress responses and social behaviours. In the present grant, we address how, from a molecular perspective, foraging accomplishes its pleiotropic functions in Drosophila social behaviours.  Social behaviours to be studied are: 1) Larval social foraging: Larval social foraging occurs under high-density conditions when 3rd instar larvae form groups who synchronize their downward digging into the liquified food. Under low-density rearing both sitters and rovers forage alone (solitary foraging) whereas under high density, sitters forage in groups (social foraging) while rovers (and larvae with the foraging gene genetically deleted) forage alone. 2) Adult social interaction duration: In groups, adult sitter flies have significantly longer interaction durations than rovers. Social isolation reduces the interaction duration of sitters but not rovers. Genetic analyses tie a number of adult social phenotypes to the foraging gene. The foraging gene is a complex gene comprising about 35kb of DNA. The foraging gene produces many gene products including 21 transcripts an approximately 9 protien isoforms.  The foraging gene is conserved across species and found in multiple systems, tissues and cells throughout development and adulthood of the fly. In the current proposal our objectives are to investigate 1) how the foraging gene's complex structure (multiple promoters, RNA transcripts and protein isoforms) play a modular role in Drosophila social behaviours and, 2) how social behaviours are regulated by interactions between the foraging gene and its epigenetic regulators (G9a, a histone methyl transferase gene, and the microRNA, miR-932), and how the social environment (e.g. social isolation) acts to change these patterns of regulation. This research will build a comprehensive and foundational understanding of how a complex gene affects multiple interacting phenotypes to generate normal individual differences in social behaviour.