Villar Angela J, Belichenko Pavel V, Gillespie Anne Marie, Kozy Heather M, Mobley William C, Epstein Charles J
Department of Pediatrics, University of California, San Francisco, San Francisco, California 94143, USA.
Mamm Genome. 2005 Feb;16(2):79-90. doi: 10.1007/s00335-004-2428-7.
The segmental trisomy model, Ts65Dn, has been a valuable resource for the study of the molecular and developmental processes associated with the pathogenesis of Down syndrome. However, male infertility and poor transmission of the small marker chromosome, T(17(16))65Dn, carrying the distal end of mouse Chromosome 16 (MMU16) are limiting factors in the efficient production of these animals for experimental purposes. We describe here the identification and preliminary characterization of mice, designated Ts[Rb(12.17(16))]2Cje, carrying a chromosomal rearrangement of the Ts65Dn genome whereby the marker chromosome has been translocated to Chromosome 12 (MMU12) forming a Robertsonian chromosome. This stable rearrangement confers fertility in males and increases the frequency of transmitted segmental trisomy through the female germline. We confirm retention of a dosage imbalance of human Chromosome 21 (HSA21)-homologous genes from App to the telomere and expression levels similar to Ts65Dn within the triplicated region. In addition, we characterized the dendritic morphology of granule cells in the fascia dentata in Ts[Rb(12.17(16))2Cje and 2N control mice. Quantitative confocal microscopy revealed decreased spine density on the dendrites of dentate granule cells and significantly enlarged dendritic spines affecting the entire population in Ts[Rb(12.17(16))]2Cje as compared to 2N controls. These findings document that the structural dendritic spine abnormalities are similar to those previously observed in Ts65Dn mice. We conclude that this new model of Down syndrome offers reproductive advantages without sacrificing the integrity of the Ts65Dn model.
节段性三体模型Ts65Dn，一直是研究与唐氏综合征发病机制相关的分子和发育过程的宝贵资源。然而，雄性不育以及携带小鼠16号染色体（MMU16）远端的小标记染色体T(17(16))65Dn传递效率低下，是高效繁育用于实验目的的这些动物的限制因素。我们在此描述了名为Ts[Rb(12.17(16))]2Cje小鼠的鉴定及初步特征，该小鼠携带Ts65Dn基因组的染色体重排，其中标记染色体已易位至12号染色体（MMU12），形成了一条罗伯逊易位染色体。这种稳定的重排赋予了雄性生育能力，并提高了通过雌性生殖系传递节段性三体的频率。我们证实，从App到端粒的人类21号染色体（HSA21）同源基因的剂量失衡得以保留，且在三倍体区域内的表达水平与Ts65Dn相似。此外，我们对Ts[Rb(12.17(16))]2Cje和二倍体（2N）对照小鼠齿状回颗粒细胞的树突形态进行了表征。定量共聚焦显微镜检查显示，与2N对照相比，Ts[Rb(12.17(16))]2Cje小鼠齿状颗粒细胞树突上的棘密度降低，且树突棘显著增大，影响了整个群体。这些发现证明，树突棘的结构异常与之前在Ts65Dn小鼠中观察到的相似。我们得出结论，这种新的唐氏综合征模型具有生殖优势，同时又不牺牲Ts65Dn模型的完整性。
