Abnormal MicroRNA Expression in Ts65Dn Hippocampus and Whole Blood: Contributions to Down Syndrome Phenotypes

Abstract

Down syndrome (DS; trisomy 21) is one of the most common genetic causes of intellectual disability, which is attributed to triplication of genes located on chromosome 21. Elevated levels of several microRNAs (miRNAs) located on chromosome 21 have been reported in human DS heart and brain tissues. The Ts65Dn mouse model is the most investigated DS model with a triplicated segment of mouse chromosome 16 harboring genes orthologous to those on human chromosome 21. Using ABI TaqMan miRNA arrays, we found a set of miRNAs that were significantly up- or downregulated in the Ts65Dn hippocampus compared to euploid controls. Furthermore, miR-155 and miR-802 showed significant overexpression in the Ts65Dn hippocampus, thereby confirming results of previous studies. Interestingly, miR-155 and miR-802 were also overexpressed in the Ts65Dn whole blood but not in lung tissue. We also found overexpression of the miR-155 precursors, pri- and pre-miR-155 derived from the miR-155 host gene, known as B cell integration cluster, suggesting enhanced biogenesis of miR-155. Bioinformatic analysis revealed that neurodevelopment, differentiation of neuroglia, apoptosis, cell cycle, and signaling pathways including ERK/MAPK, protein kinase C, phosphatidylinositol 3-kinase, m-TOR and calcium signaling are likely targets of these miRNAs. We selected some of these potential gene targets and found downregulation of mRNA encoding Ship1, Mecp2 and Ezh2 in Ts65Dn hippocampus. Interestingly, the miR-155 target gene Ship1 (inositol phosphatase) was also downregulated in Ts65Dn whole blood but not in lung tissue. Our findings provide insights into miRNA-mediated gene regulation in Ts65Dn mice and their potential contribution to impaired hippocampal synaptic plasticity and neurogenesis, as well as hemopoietic abnormalities observed in DS.

Integrated microRNA and protein expression analysis reveals novel microRNA regulation of targets in fetal down syndrome

“…In the present study, the challenge was to map miRNAs to specific gene targets and the molecular networks they regulate. Studies have provided insights into miRNA-mediated gene regulation in Ts65Dn mice, and the potential contribution to impaired hippocampal synaptic plasticity and neurogenesis, and the hemopoietic abnormalities observed in DS (20,21). The present study found evidence for the functional importance of several previously unknown miRNAs in DS.…”

Autoimmune Predisposition in Down Syndrome May Result from a Partial Central Tolerance Failure due to Insufficient Intrathymic Expression of AIRE and Peripheral Antigens

“…Indeed, chromosome 21 codes for at least seven miRNAs: miR-99a, let-7c, miR-125b-2, miR-155 and miR-802, and miR-nov1 and miR-nov2 (45). Although the targets and pathways of chromosome 21 miRNAs have not been determined, it has been proposed that overexpression of these miRNAs may contribute to the observed DS phenotypes, including increased incidence of autoimmune diseases (46)(47)(48)(49). Of note, it has been recently reported that the regulation of pGE is under the control of miRNAs.…”

Weaker control of the electrical properties of cerebellar granule cells by tonically active GABAA receptors in the Ts65Dn mouse model of Down’s syndrome

“…It is possible that in DS, disomic Gabrb3 is modified by overexpressed trisomic microRNAs (miRNAs) or transcription factors located on Hsa21 [2,3,28,80-82]. The trisomic region of Mmu16 in Ts65Dn mice harbours two of the miRNAs located on Hsa21, mir-155 and mir-802, [2,80,81,83,84] and these are overexpressed in Ts65Dn hippocampus and prefrontal cortex [80]. However, they are not predicted to target human or mouse Gabrb3 mRNAs [85-87].…”