Prenatal Genomics and Fetal Therapy Section, Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
Center for Health Protection, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Biol Psychiatry. 2023 Jul 1;94(1):84-97. doi: 10.1016/j.biopsych.2023.02.012. Epub 2023 Mar 14.
Despite successful preclinical treatment studies to improve neurocognition in the Ts65Dn mouse model of Down syndrome, translation to humans has failed. This raises questions about the appropriateness of the Ts65Dn mouse as the gold standard. We used the novel Ts66Yah mouse that carries an extra chromosome and the identical segmental Mmu16 trisomy as Ts65Dn without the Mmu17 non-Hsa21 orthologous region.
Forebrains from embryonic day 18.5 Ts66Yah and Ts65Dn mice, along with euploid littermate controls, were used for gene expression and pathway analyses. Behavioral experiments were performed in neonatal and adult mice. Because male Ts66Yah mice are fertile, parent-of-origin transmission of the extra chromosome was studied.
Forty-five protein-coding genes mapped to the Ts65Dn Mmu17 non-Hsa21 orthologous region; 71%-82% are expressed during forebrain development. Several of these genes are uniquely overexpressed in Ts65Dn embryonic forebrain, producing major differences in dysregulated genes and pathways. Despite these differences, the primary Mmu16 trisomic effects were highly conserved in both models, resulting in commonly dysregulated disomic genes and pathways. Delays in motor development, communication, and olfactory spatial memory were present in Ts66Yah but more pronounced in Ts65Dn neonates. Adult Ts66Yah mice showed milder working memory deficits and sex-specific effects in exploratory behavior and spatial hippocampal memory, while long-term memory was preserved.
Our findings suggest that triplication of the non-Hsa21 orthologous Mmu17 genes significantly contributes to the phenotype of the Ts65Dn mouse and may explain why preclinical trials that used this model have unsuccessfully translated to human therapies.
尽管在唐氏综合征的 Ts65Dn 小鼠模型中进行了成功的临床前治疗研究以改善神经认知，但向人类的转化却失败了。这引发了对 Ts65Dn 小鼠作为黄金标准的适当性的质疑。我们使用了携带额外染色体和相同片段性 Mmu16 三体的新型 Ts66Yah 小鼠，而没有 Mmu17 非 Hsa21 同源区。
从胚胎期 18.5 天的 Ts66Yah 和 Ts65Dn 小鼠以及正常二倍体同窝对照的前脑中提取用于基因表达和途径分析。在新生儿和成年小鼠中进行行为实验。由于雄性 Ts66Yah 小鼠具有生育能力，因此研究了额外染色体的亲本来源传递。
45 个编码蛋白的基因映射到 Ts65Dn Mmu17 非 Hsa21 同源区；71%-82%在大脑前发育过程中表达。这些基因中有几个在 Ts65Dn 胚胎前脑中独特过表达，导致失调基因和途径发生重大差异。尽管存在这些差异，但两种模型中的主要 Mmu16 三体效应高度保守，导致共同失调的二倍体基因和途径。Ts66Yah 新生小鼠的运动发育、交流和嗅觉空间记忆延迟，但在 Ts65Dn 中更为明显。成年 Ts66Yah 小鼠表现出轻度的工作记忆缺陷以及在探索行为和空间海马记忆方面的性别特异性效应，而长期记忆得以保留。
我们的研究结果表明，非 Hsa21 同源 Mmu17 基因的三倍体显著促成了 Ts65Dn 小鼠的表型，这可能解释了为什么使用该模型进行的临床前试验未能转化为人类治疗。
