PLX143145

GSE138468: Dosage normalization of the Down syndrome critical causative gene Dyrk1a and Kcnj6

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

Down syndrome (DS) is the most frequently occurred human chromosomal disorder for mental retardation. Previous studies have indicated that normalizing the dosage of the trisomic gene Dyrk1a or Kcnj6 significantly improved the hippocampal-dependent learning and memory deficits in DS. However, normalizing both genes eliminated specific rescue effects achieved by individual gene normalization. The underlying mechanisms of the gene dosage interactions have not been revealed yet. In this study, we generated DS mice with either individual or both genes normalized to euploid by compounding a novel Kcnj6 KO mouse and/or Dyrk1a KO mouse with the DS mouse model Dp(16)1Yey. Double normalization achieved better rescue effects on DS excitation/inhibition imbalance than normalizing Dyrk1a only when assessing the levels of excitation/inhibition-related proteins, and no counter interactions were observed. However, in the following hippocampal transcriptome analysis, while normalizing Dyrk1a caused a general down-regulation of genes, further normalizing Kcnj6 caused a general up-regulation of genes. KEGG pathway analysis of the differentially expressed genes enriched terms tight junction and cell adhesion molecules. Specifically, one of counter-affected genes which encoding the tight-junction protein claudin-14 is located in the DS critical region and had been reported to escape the 1.5 fold rule in another DS mouse model as well. Immunohistology study suggested that altered claudin-14 expression might affect the neuron niche environment via stiffness or extracellular homeostasis of calcium or other cations. Our results raised the potential critical roles of neuron extracellular environment in the pathology of DS hippocampal-depenent deficits. SOURCE: Xiaoling Jiang (jianggenetics@163.com) - Guangzhou Women and Children's Medical Center