REPOSITORY OF MOUSE MODELS FOR CYTOGENETIC RESEARCH

全国尤尼斯·肯尼迪·施莱佛智力和发育障碍分支 儿童健康和人类发展研究所（NICHD）赞助研究和研究培训 旨在预防和改善智力和发育残疾。 该计划支持，生物医学，生物行为，行为和转化的病因学，病理生理学，筛查，预防，治疗和这些疾病的流行病学研究。 唐氏综合征（DS; 21三体）是智力残疾最常见的遗传原因之一，每年影响美国700名婴儿中的1名（1，2），或估计总数约为250，000 2008年美国唐氏综合症患者（3）。由于大多数个体中存在21号染色体的3个拷贝，这种情况的特征是除了智力残疾之外还涉及多个器官系统。唐氏综合征所致智力障碍的分子和细胞基础一直是深入研究的主题，并且存在该疾病的小鼠模型。 细胞遗传学疾病小鼠模型库（“小鼠库”）始于20世纪70年代，用于生成和分发细胞遗传学疾病的小鼠模型，特别强调唐氏综合征（DS; 21三体）。 与DS相关的小鼠模型的创建始于20世纪70年代，并随着小鼠16号染色体（Mmu 16）和人类21号染色体（Hsa 21）之间的遗传同线性的证明而继续，这导致使用16三体小鼠（Ts 16）作为DS相关研究的模型。 随着随后对小鼠和人类基因组的遗传解剖，Hsa 21上存在的其他基因也定位于小鼠染色体17和10（Mmu 17和Mmu 10）。 在20世纪80年代，根据与NICHD的合同，产生了一些同线染色体片段的部分三体。 这些部分三体之一，命名为Ts 65 Dn，被证明包括大约150个基因，位于被认为是Hsa 21的“唐氏综合征关键区域”。 随后，根据NICHD合同，这些小鼠被生产并分发给NICHD批准接收它们的研究者。 在过去的30年里，各种研究人员已经产生了其他相关的DS模型。 这些 包括但不限于Ts 1Cje、Ts 2Cje、Ts 1 Rhr、Ms 1 Rhr、Tc 1等。 当这些 菌株和股票已提供给研究界，建立一个中央 储存库已确保其维持在适当的遗传背景和 经NICHD批准后，应要求及时分发给研究者。 这些小鼠品系中的许多在冷冻保存下维持。2010年，NICHD重新发布了“细胞遗传学疾病小鼠模型库”合同，大幅增加了投资，以确保研究界及时获得并增加细胞遗传学疾病小鼠模型的可用性，特别是Ts 65 Dn，并确保增加实验努力，以修改各种菌株的现有遗传背景，以增加研究人员的可用性和易用性。在2013年4月举行的研讨会“推进唐氏综合征患者阿尔茨海默病的治疗”上，来自阿尔茨海默病和DS研究和倡导社区的参与者对整个研究社区现有模型系统（Ts 65 Dn小鼠除外）的有限可用性表示担忧。自那次会议以来，部分重复菌株Dup（16）Yey、Dup（17）Yey和Dup（10）Yey已成为 可用，现在是这个鼠标存储库的一部分。每一个菌株都有一个复制体 与HSA 21同线的3个小鼠染色体区域之一，Dup（16）Yey代表与人21号染色体同线的最大数量的鼠基因。截至2017年，DS的小鼠模型综述见（4），见下图。最近，已经创建了DS的TcMAC 21“人源化”小鼠模型，其中Hsa 21插入小鼠人工染色体（具有小鼠着丝粒和端粒）-这是稳定传播的，因此小鼠具有大约相当于3个拷贝的21号染色体（2个小鼠，1个人类），并具有人类疾病的许多特征（5）。随着2018年6月跨NIH INCLUDE（调查整个生命周期中的并发症以了解唐氏综合征）项目的启动，人们对支持基础科学，队列发展和临床试验领域的唐氏综合征研究重新产生了兴趣。为了支持该项目的组成部分1，其重点是进行有针对性的、高风险的、高回报的基础科学研究，以了解21号染色体生物学和DS中的共现病症，迫切需要确保复制人类特征的病症的高质量小鼠模型的可用性。 结合对Ts 65 Dn模型在建模人类三体性方面的局限性的关注，重要的是将新模型添加到该小鼠库中。

The Intellectual and Developmental Disabilities (IDD) Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) sponsors research and research training aimed at preventing and ameliorating intellectual and developmental disabilities. The program supports , biomedical, biobehavioral, behavioral, and translational research in etiology, pathophysiology, screening, prevention, treatment, and epidemiology of these disorders. Down syndrome (DS; trisomy 21) is one of the most common genetic causes of intellectual disability, affecting ~1 in 700 babies in the U.S. each year (1, 2), or an estimated total of ~250,000 Americans living with Down syndrome in 2008 (3). Caused by the presence of 3 copies of chromosome 21 in most individuals, this condition is characterized by multiple organ system involvement in addition to intellectual disability. The molecular and cellular bases of intellectual disability due to Down syndrome have been a topic of intensive study, and murine models of the disease exist. The Repository of Mouse Models for Cytogenetic Disorders (“Mouse Repository”) began in the 1970s to generate and distribute mouse models for cytogenetic disorders, with special emphasis on Down syndrome (DS; trisomy 21). The creation of mouse models relevant to DS began in the 1970s and continued with the demonstration of genetic synteny between a segment of mouse chromosome 16 (Mmu16) and human chromosome 21 (Hsa21), which led to the use of the trisomy 16 mouse (Ts16) as a model for studies relevant to DS. With the subsequent genetic dissection of both mouse and human genomes, other genes present on Hsa21 were localized to mouse chromosomes 17 and 10 (Mmu17 and Mmu10) as well. Partial trisomies for a number of syntenic chromosomal segments were generated in the 1980s, under contract to NICHD. One of these partial trisomies, designated Ts65Dn, proved to include approximately 150 genes located in what is considered the “Down syndrome critical region” of Hsa21. Subsequently, these mice were produced and distributed, under an NICHD contract, to investigators approved for receipt of them by NICHD. During the last 30 years, various investigators have generated other models relevant to DS. These include, but are not limited to, Ts1Cje, Ts2Cje, Ts1Rhr, Ms1Rhr, Tc1, and others. When these strains and stocks have been made available to the research community, the creation of a central repository has ensured their maintenance on appropriate genetic backgrounds and their distribution to investigators upon request in a timely manner and subsequent to approval by NICHD. Many of these mouse strains are maintained under cryopreservation. In 2010, the NICHD reissued the contract “A Repository of Mouse Models of Cytogenetic Disorders” with a substantial increase in investment to ensure timely access to and increased availability of mouse models for cytogenetic disorders, particularly Ts65Dn, to the research community, and to ensure increased experimental efforts to modify the existing genetic backgrounds for the various strains to increase availability and ease of use by investigators. At a workshop “Advancing Treatment for Alzheimer Disease in Individuals with Down Syndrome” held in April, 2013, the participants from the Alzheimer disease and DS research and advocacy communities expressed concern with the limited availability of existing model systems (other than the Ts65Dn mouse) to the research community at large. Since that meeting, the partial duplication strains Dup(16)Yey, Dup(17)Yey, and Dup(10)Yey have become available and are now part of this Mouse Repository. Each of these strains contains a duplication of one of the 3 mouse chromosome regions that are syntenic to HSA21, with Dup(16)Yey representing the largest number of murine genes syntenic to the human chromosome 21 Mouse models for DS available as of 2017 are reviewed in (4) and see Figure below. More recently, the TcMAC21 “humanized” mouse model of DS has been created with Hsa21 inserted in a mouse artificial chromosome (with mouse centromere and telomere)—this is stably transmitted so mice have approximately the equivalent of 3 copies of chromosome 21 (2 mouse, one human), and share many features of the human condition (5). With the launch of the trans-NIH INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) project in June 2018, there has been a renewed interest in supporting Down syndrome research in the domains of basic science, cohort development, and clinical trials. To support component 1 of the project, which is focused on conducting targeted, high- risk, high-reward basic science studies to understand chromosome 21 biology and the co-occurring conditions in DS, there is a pressing need to ensure the availability of high-quality murine models of the condition that replicate human traits. Combined with concerns about the Ts65Dn model’s limitations with regard to modeling the human trisomy, it is important that new model(s) be added to this Mouse Repository.