Horseman, pass by: finding post-developmental functions of essential genes

描述（由申请人提供）：生物是高效的，经常重复使用相同的基因多次用于不同的目的。如果一个基因的一个功能是必不可少的，那么这个突变体的死亡或被逮捕就会掩盖其他后来的功能。这种对基本基因后期功能的盲点在神经系统中尤其麻烦。大多数神经元不能从干细胞群中再生，因此必须在生物体的整个生命周期中存活并保持其信息处理能力。为了完成这一生存壮举，神经元必须维持其结构，并在受损时进行修复。但是，由于维持和再生发生在发育之后，因此对维持和再生老化神经元的基本基因的贡献知之甚少。本项目在秀丽隐杆线虫中开发了一种新的策略来实现基因失活的时空控制。通过使用这种策略，有可能绕过对必需基因的初始要求。此外，与现有的条件或诱导基因敲除技术相比，该策略有一个关键优势：它与基因筛选兼容。因此，这种策略打破了阻碍基因筛选发现基本基因后期功能的障碍。这一重要的进展将使必要基因的多种功能在任何地方都能被梳理出来。本项目利用这一策略来发现神经元中必要基因的功能，重点关注细胞的存活、发育、轴突和突触的维持以及再生。这些实验应该确定一组共同因素，这些因素有助于在发育结束后很长一段时间内保持和恢复所有神经系统的神经功能。许多神经系统疾病的一个特点是发病延迟。此外，即使在没有已知疾病的情况下，与年龄相关的神经系统功能衰退也会发生。这些观察结果表明，成熟神经系统的发育后变化导致疾病易感性和功能丧失。通过在神经元发育完成后使其基因失活，该项目将确定老化神经元中保守基因的关键功能，对衰老、疾病易感性和药物靶点发现具有广泛的相关性。

DESCRIPTION (provided by applicant): Living organisms are highly efficient and often reuse the same genes multiple times for different purposes. If one function of a gene is essential, death or arrest of the mutant masks other, later functions. This blind spot to later functions of essential genes is particularly troublesome in the nervous system. Most neurons can't be renewed from stem cell populations and therefore must survive and preserve their information- processing capabilities throughout the life of the organism. To accomplish this feat of survival, neurons must maintain their structure and repair it when damaged. But because maintenance and regeneration occur after development, the contribution of essential genes to maintaining and regenerating aging neurons is poorly understood. This project develops a novel strategy in C. elegans for achieving spatial and temporal control of gene inactivation. By using this strategy, it is possible to circumvent the initial requirement for essential genes. Further, the strategy has a critical advantage over existing techniques for making conditional or inducible knockouts: it is compatible with genetic screens. Thus, this strategy breaks down the barrier that prevents genetic screens from finding the later functions of essential genes. This important advance will enable multiple functions of essential genes to be teased apart wherever they occur. This project deploys this strategy to discover the function of essential genes specifically in neurons, focusing on cell survival, development, maintenance of axons and synapses, and regeneration. These experiments should identify a set of common factors that help preserve and restore neural function in all nervous systems, long after development has ended. A hallmark of many neurological diseases is delayed onset. Further, age-related decline in nervous system function occurs even in the absence of known disease. These observations suggest that post-developmental changes in the mature nervous system result in disease susceptibility and loss of function. By inactivating genes in neurons after their development is complete, this project will identify critical functions for conserved genes in aging neurons, with broad relevance for aging, disease susceptibility, and drug target discovery. PUBLIC HEALTH RELEVANCE: As neurons age, they need to maintain their function and structure, and repair themselves when damaged. This project will develop a novel genetic technology for the spatial and temporal regulation of gene inactivation. By inactivating genes in neurons after their development is complete, this project will identify critical functions for conserved genes in aging neurons, with broad relevance for aging, disease susceptibility, and drug target discovery.