Use of ENU mutagenesis to identify novel genes required for forebrain development

描述(申请人提供)：人类的前脑是负责人类许多独特品质的器官，包括推理、情感和记忆。这种复杂的器官可能会受到一系列疾病的困扰，从会带来终生后果的发育异常，到神经退化或肿瘤形成等较晚发病的疾病。尽管这一点很重要，但关于大脑发育的分子控制，还有很多需要学习的地方。进一步了解大脑的一种方法是发现更多与大脑发育、功能和疾病有关的遗传成分。小鼠，特别是它独特的遗传工具，是人类生理学的极好模型，最近基因组技术的进步使我们能够将大规模的遗传方法应用于大脑研究。这项提议将在突变实验中使用小鼠遗传工具来识别并开始表征小鼠大脑正常发育和功能所需的新基因。小鼠的Enu突变是一种既定的工具，可以创造常染色体隐性突变，类似于在人类群体中发现的突变，然后可以被定位和克隆。该提案的目的是(1)筛选ENU诱导的小鼠中影响大脑发育的突变，以及(2)开始表征初步研究中已经确定的两个突变。识别大脑发育所需的新等位基因可能有助于我们目前对大脑发育和功能的了解。我们对人类疾病理解的最新进展表明，个体的基因构成与特定疾病的病因或易感性之间存在着重要的联系。进一步研究人类疾病根源的一种方法是使用类似的实验动物模型来发现与特定疾病相关的新基因。通过识别更多的潜在疾病原因，可以阐明这些基因的功能，从而增加对人类疾病的最终治疗和解决方案。这项提议旨在揭示大脑发育和疾病的一些基本机制。

DESCRIPTION (provided by applicant): The human forebrain is the organ responsible for many of our uniquely human qualities, including reasoning, emotion and memory. This complex organ can be afflicted by a wide array of diseases from developmental abnormalities with lifelong consequences to later onset diseases such as neurodegeneration, or tumorigenesis. Despite this importance, there is much to learn about the molecular control of brain development. One approach to gain further understanding of the brain is to uncover more of the genetic components involved in its development, function and disease. The mouse, especially with its unique genetic tools, serves as an excellent model for human physiology and recent advances in genomic technologies allow us to apply large scale genetic approaches to studies of the brain. This proposal will use mouse genetic tools in a mutagenesis experiment to identify and begin to characterize novel genes required for normal development and function of the mouse brain. ENU mutagenesis in the mouse is an established tool to create autosomal recessive mutations, similar to those found in the human population, which can then be mapped and cloned. The aims of the proposal are to (1) screen for ENU- induced mutations in the mouse which affect brain development, and (2) begin to characterize two of the mutations already identified in preliminary studies. The identification of new alleles required for brain development is likely to contribute to our current state of understanding of the brain's development and function. Recent advances in our understanding of human disease have demonstrated the significant connection between individual genetic makeup and causation of, or predisposition to, specific diseases. One way to further study the roots of human disease is the use of similar experimental animal models to discover new genes related to specific disorders. By identifying more of the underlying causes of disease, the function of these genes can be elucidated, leading to increased treatments for the ultimate treatment and resolution of human disorders. This proposal is designed to uncover some of the fundamental mechanisms in brain development and disease.