Triplications of human chromosome 21 orthologous regions in mice result in expansion of megakaryocyte-erythroid progenitors and reduction of granulocyte-macrophage progenitors.
Triplications of human chromosome 21 orthologous regions in mice result in expansion of megakaryocyte-erythroid progenitors and reduction of granulocyte-macrophage progenitors.
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小鼠中人类 21 号染色体直系同源区域的三倍体导致巨核细胞-红系祖细胞的扩增和粒细胞-巨噬细胞祖细胞的减少
DOI：
10.18632/oncotarget.23463
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发表时间：
2018-01-12
期刊：
影响因子：
--
通讯作者：
Yu YE
中科院分区：
文献类型：
--
作者：
Liu C;Yu T;Xing Z;Jiang X;Li Y;Pao A;Mu J;Wallace PK;Stoica G;Bakin AV;Yu YE
唐氏综合征（DS）患者经常有造血异常，包括短暂性骨髓增生性疾病和急性巨核母细胞白血病，这些疾病通常伴有获得性GATA1突变，产生一种截断的蛋白GATA1。基于人类第21号染色体（Hsa21）与小鼠基因组中位于小鼠第10号染色体（Mmu10）、Mmu16和Mmu17上的三个区域的同步保守性，我们利用小鼠建立了DS模型。为了评估Hsa21基因同源物剂量增加对造血系统的影响，我们在Dp(10)1Yey/+;Dp(16)1Yey/+；在Mmu10、Mmu16和Mmu17上携带横跨整个Hsa21同源区域的复制的Dp(17)1Yey/+模型，以及Dp(10)1Yey/+、Dp(16)1Yey/+、Dp(17)1Yey/+；Gata1Yeym2模型携带我们设计的Gata1s突变。两种模型均表现为贫血、巨噬细胞增多和骨髓增生性疾病。与人DS相似，两种模型中巨核细胞-红细胞祖细胞（MEPs）和粒细胞-单核细胞祖细胞（gmp）分别显著增加和减少。随后在Dp(16)1Yey/+模型中对上述所有表型的鉴定表明，致病剂量敏感基因位于Mmu16上的Hsa21同源区。因此，我们在这里首次揭示了小鼠中人类21三体相关的主要染色体片段改变可以导致MEP增加和GMP群体减少，模拟了DS中这些髓系祖细胞的动态变化。这些模型将为揭示ds相关骨髓增殖性疾病的分子和细胞机制，特别是确定人类21三体如何导致MEPs扩增以及这种改变如何导致骨髓增殖性疾病提供关键系统。
Individuals with Down syndrome (DS) frequently have hematopoietic abnormalities, including transient myeloproliferative disorder and acute megakaryoblastic leukemia which are often accompanied by acquired GATA1 mutations that produce a truncated protein, GATA1s. The mouse has been used for modeling DS based on the syntenic conservation between human chromosome 21 (Hsa21) and three regions in the mouse genome located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. To assess the impact of the dosage increase of Hsa21 gene orthologs on the hematopoietic system, we characterized the related phenotype in the Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+ model which carries duplications spanning the entire Hsa21 orthologous regions on Mmu10, Mmu16 and Mmu17, and the Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+;Gata1Yeym2 model which carries a Gata1s mutation we engineered. Both models exhibited anemia, macrocytosis, and myeloproliferative disorder. Similar to human DS, the megakaryocyte-erythrocyte progenitors (MEPs) and granulocyte-monocyte progenitors (GMPs) were significantly increased and reduced, respectively, in both models. The subsequent identification of all the aforementioned phenotypes in the Dp(16)1Yey/+ model suggests that the causative dosage sensitive gene(s) are in the Hsa21 orthologous region on Mmu16. Therefore, we reveal here for the first time that the human trisomy 21-associated major segmental chromosomal alterations in mice can lead to expanded MEP and reduced GMP populations, mimicking the dynamics of these myeloid progenitors in DS. These models will provide the critical systems for unraveling the molecular and cellular mechanism of DS-associated myeloproliferative disorder, and particularly for determining how human trisomy 21 leads to expansion of MEPs as well as how such an alteration leads to myeloproliferative disorder.
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影响因子：
2.5
作者：
Bhutta, Mahmood F.;Cheeseman, Michael T.;Herault, Yann;Yu, Yuejin E.;Brown, Steve D. M.
通讯作者：
Brown, Steve D. M.
影响因子：
4.6
作者：
Guedj F;Pennings JL;Massingham LJ;Wick HC;Siegel AE;Tantravahi U;Bianchi DW
通讯作者：
Bianchi DW
影响因子：
7.9
作者：
Block A;Ahmed MM;Dhanasekaran AR;Tong S;Gardiner KJ
通讯作者：
Gardiner KJ
DOI：
10.1007/s00335-016-9661-8
发表时间：
2016-12
期刊：
Mammalian genome : official journal of the International Mammalian Genome Society
影响因子：
--
作者：
Gupta M;Dhanasekaran AR;Gardiner KJ
通讯作者：
Gardiner KJ
影响因子：
6.1
作者：
Ahn, Kyoung-Jin;Jeong, Hey Kyeong;Song, Woo-Joo
通讯作者：
Song, Woo-Joo