Abstract
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.
Highlights
Human trisomy 21, the most common human aneuploidy compatible with postnatal survival, occurs in approximately one out of 700–1000 live births [1, 2]
Recombination between pTVGata1 and the Gata1 locus in embryonic stem (ES) cells led to the replacement of a genomic region containing exon 2 of the gene with a neomycin-resistance gene cassette flanked by two loxP sites (Figure 2A)
Germline transmission was established for four ES cell lines that carried Gata1Yeym2
Summary
Human trisomy 21, the most common human aneuploidy compatible with postnatal survival, occurs in approximately one out of 700–1000 live births [1, 2]. This chromosomal anomaly causes a constellation of developmental abnormalities, classified as Down syndrome (DS). It has been demonstrated that children with DS who develop TMD and AMKL have acquired somatic mutations in exon 2 of the GATA1 gene on the X chromosome, which lead to the generation of a mutant protein, GATA1s [6, 7]. The GATA1s germline mutation is associated with impaired erythropoiesis [8, 9]
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