Regulation of Neuronal Differentiation by Micropeptides

了解组织如何生长和发育是发育生物学的核心问题。神经系统是大多数动物中最复杂的组织之一，包含一些最高度专业化的细胞类型。与所有成人组织一样，神经系统的特化细胞来源于一组干细胞，这些干细胞可以在发育中的胚胎中找到，也可以在后期发育阶段找到，包括人类的成人大脑。这些神经干细胞以精确控制的方式分裂以产生神经元，神经元是神经系统的功能细胞。已经做了很多研究来鉴定在神经元中被激活的基因，这些基因反过来又调节神经元功能所必需的其他基因。之前，我们发现了一个基因，lola，它以相反的方式起作用-即它通过关闭干细胞基因来维持细胞的神经元身份。lola基因突变的动物会患上脑肿瘤，这是神经元恢复为干细胞的结果。为了了解洛拉是如何调节这些效应的，我们进一步寻找了与洛拉相互作用的基因。使用这种方法，我们确定了一个有趣的基因，copacobana（copa），我们认为它参与了萝拉功能的调节。与大多数基因不同的是，copa基因含有细胞制造大型蛋白质产物所需的指令，它被分成一系列较小的功能单位，称为开放阅读框架（smORF），这使得该基因能够制造多个小肽。类似的小肽先前已被发现参与各种生物过程，然而，copa是第一个在神经系统中观察到的此类例子。为了确切地了解copa在神经元发育中的作用，我们打算利用遗传技术来创造出去除copa的突变果蝇。通过观察这些突变体神经系统的发育，我们将能够确定copa的作用及其与lola的关系。基因中smORF的存在是很难预测的。我们打算利用最新发展的分子生物学技术来全面研究copa的功能区域，这将使我们能够更全面地了解它在大脑发育中的作用。深入了解脑组织是如何构建的，对于理解先天性疾病（如小头畸形）以及退行性疾病（如阿尔茨海默氏症）可能出现的问题至关重要。在某些癌症中，据认为细胞经历了一个类似干细胞状态的逆转，正如我们在lola突变体中所观察到的那样。因此，这个项目可以帮助我们了解这个过程是如何发生的。我们希望这个项目可能有助于为这些疾病和其他疾病的治疗方法的发展提供信息。此外，像copa公司生产的小分子肽也有可能用于药理学或工业用途。含有smORF的基因很难识别，目前只有少数几个验证这种现象的例子。通过识别和表征在大脑中活跃的功能肽，我们正在推进我们对一个迷人的新生生物学领域的理解。识别smORF作用的原理证明有可能影响几乎所有的生物科学领域。

Understanding how tissues grow and develop is a central question in developmental biology. The nervous system is one of the most complex tissues in most animals, and contains some of the most highly specialised cell types. As with all adult tissues, the specialised cells of the nervous system are derived from a set of stem cells which can be found in developing embryos, as well as in later developmental stages, including the adult brain in humans. These neural stem cells divide in a precisely controlled manner to produce neurons, which are the functional cells of the nervous system. Much research has been done to identify genes which are activated in neurons, which in turn regulate further genes that are necessary for neuronal function. Previously, we identified a gene, lola, which acts in the opposite manner - i.e. it maintains cell's neuronal identity by switching off stem cell genes. Animals that are mutants for lola develop brain tumours which are the result of neurons reverting back to stem cells. In an effort to understand how lola mediates these effects, we looked for further genes that interact with lola. Using this approach, we identified an interesting gene, copacobana (copa), which we believe is involved in the regulation of Lola function. In contrast to most genes, which contain the instructions required for the cell to make a large protein product, copa is divided in to a series of smaller functional units called open reading frames (smORFs), which allows this gene to make multiple small peptides. Similar small peptides have been found previously to be involved in various biological processes, however, copa is the first example of its kind to be observed in the nervous system. To understand exactly how copa is functioning in the development of neurons, we are intending to use genetic techniques to create mutant fruit flies in which copa is removed. By observing the development of the nervous system in these mutants, we will be able to determine the action of copa and its relationship to lola. The presence of smORFs within a gene is very difficult to predict. We intend to use recently developed molecular biology techniques to fully characterise the functional regions of copa, which will allow us to more fully appreciate its role in brain development.In depth knowledge of how brain tissues are built is vital for understanding what can go wrong in congenital conditions such as microcephaly, as well as degenerative diseases such as Alzheimer's. In certain cancers, it is thought that cells undergo a reversion to a stem cell like state as observed with our lola mutants. Therefore, this project may help us to understand how that process is able to occur. We hope that this project may help to inform the development of therapeutics for these conditions and others. Furthermore, there is potential for small peptides such as the ones made by copa to be used for pharmacological or industrial purposes. smORF-containing genes are very difficult to identify, and there are currently only a handful of validated examples of this phenomenon. By identifying and characterising functional peptides which are active in the brain we are advancing our understanding of a fascinating nascent biological field. Identifying proof-of-principle of smORF action has the potential to impact almost all areas of bioscience.