REPOSITORY OF MOUSE MODELS FOR CYTOGENETIC RESEARCH

尤尼斯·肯尼迪·施莱弗国家基金会智力和发育障碍(IDD)分会 儿童健康与人类发展研究所(NICHD)赞助研究和研究培训 旨在预防和改善智力和发育障碍。这个 计划支持生物医学、生物行为、行为和翻译 该病的病因学、病理生理学、筛查、预防、治疗和流行病学研究 这些障碍。 唐氏综合症(DS；21三体)是导致智力残疾的最常见的遗传原因之一， 在美国，每年每700名婴儿中就有1人受到影响(1，2)，估计总数约为250,000人 2008年美国唐氏综合症患者(3)。由3个拷贝的染色体引起的 21在大多数个体中，这种情况的特征是多器官系统受累 除了智力上的残疾。智力障碍的分子和细胞基础 由于唐氏综合征一直是一个深入研究的主题，并且存在该疾病的小鼠模型。 小鼠细胞遗传学疾病模型库(“小鼠库”)始于20世纪70年代， 建立和分发细胞遗传学疾病的小鼠模型，特别强调Down 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， 继续演示小鼠16号染色体的一段之间的遗传同步性 (Mmu16)和人类21号染色体(Hsa21)，这导致了16三体小鼠(TS16)作为 与DS相关的研究模型。随后对老鼠和人类进行了基因解剖 基因组，Hsa21上存在的其他基因定位于小鼠的17号和10号染色体(Mmu17和 也是如此。一些同线染色体片段的部分三体在 20世纪80年代，根据与NICHD的合同。这些部分三体之一，命名为Ts65Dn，被证明是 包括大约150个基因，它们位于被认为是“唐氏综合症”的地方 Hsa21的“临界区域”。随后，这些小鼠在NICHD下被制造和分配 合同，提供给经NICHD批准接收的调查人员。 在过去的30年里，不同的研究人员建立了其他与DS相关的模型。这些 包括但不限于Ts1Cje、Ts2Cje、Ts1Rhr、Ms1Rhr、Tc1等。当这些 已经向研究界提供了菌株和种群，创建了一个中央 储存库确保了它们在适当的遗传背景上的维护和它们的 经NICHD批准后，应要求及时分发给调查人员。 其中许多 小鼠的品系被保存在超低温保存下。2010年，NICHD重新颁发了合同“A 《细胞遗传学疾病小鼠模型资料库》，大幅增加对 确保及时获得并提高细胞遗传学小鼠模型的可用性 疾病，特别是Ts65Dn，向研究界提供，并确保增加实验 努力修改各种菌株的现有遗传背景，以增加可获得性 以及调查人员的易用性。在一个名为《推进阿尔茨海默病治疗》的研讨会上 2013年4月举行的唐氏综合症患者研讨会，来自阿尔茨海默病的参与者 DS研究和倡导团体对可获得的有限的 现有的模型系统(除Ts65Dn鼠标外)向广大研究界提供。从那以后 会议，部分复制菌株DUP(16)YEY、DUP(17)YEY和DUP(10)YEY已成为 可用，现在是此鼠标存储库的一部分。这些菌株中的每一个都含有一个副本 与HSA21同线的3个小鼠染色体区域之一，其中DUP(16)Yey代表 与人类21号染色体共线的最大数量的小鼠基因--DS小鼠模型 第(4)项中对截至2017年的可用数据进行了审查，见下图。最近，TcMAC21 通过在人工小鼠中插入Hsa21，建立了人源化的DS小鼠模型 染色体(与小鼠着丝粒和端粒)-这是稳定传递的，所以小鼠有 大约相当于21号染色体的3个副本(2只小鼠，1个人)，共享许多 人类状况的特征(5)。 随着跨NIH的启动，INCLUDE(调查共同发生的情况 了解唐氏综合症的寿命)项目于2018年6月开始，重新引起了人们的兴趣 在基础科学领域支持唐氏综合症研究，队列发展，以及 临床试验。为了支持该项目的组成部分1，其重点是开展有针对性的活动， 高风险、高回报的基础科学研究，以了解21号染色体的生物学和 在DS共存的情况下，迫切需要确保高质量的可用 复制人类特征的条件的小鼠模型。再加上对 Ts65Dn模型在模拟人类三体方面的局限性，重要的是 新模型(S)将添加到此鼠标库中。

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.