Argonaute2 in excitatory neurons functionally regulates cellular metabolism and cerebral vascularization during brain development

点击翻译按钮获取中文摘要

Argonaute2 (Ago2) processes an endoribonuclease activity and is involved in microRNA pathway, which plays an important role in regulation of the gene expression upon pathophysiological stresses. Ago2 deletion in mice results in abnormal formation of the CNS and early death of prenatal embryos, suggesting an essential role of Ago2 in the CNS development. Our promising preliminary data show that loss of Ago2 in Vglut2-expressing excitatory neurons (Vglut2-Cre, Ago2flox/flox mice), but not in Vgat-expressing inhibitory neurons (Vgat-Cre, Ago2flox/flox mice), 1) disturbs mouse development and triggers early death of postnatal mice; 2) impairs cellular metabolism, including mitochondrial function, in hippocampus neurons; 3) strongly disrupts the brain blood vessel formation in the developing cerebral cortex; 4) alters the expression of Cadm1, Mecp2, and Ucp2 genes, which are critical for neuronal and synaptic function during development and contain target sites for Ago2-dependent miRNAs, like microRNA-22 (MiR-22), miR-24, miR-124, and miR-128. Based on our preliminary studies, we hypothesize that Ago2 as an endoribonuclease protein and a regulator of miRNA-mediated gene silencing contributes to neuronal development and brain vascularization. Therefore, the overall scientific goal of this proposal is to find out the functional roles of Ago2 in excitatory neurons during development. We will investigate how Ago2 as an endoribonuclease protein and a regulator of miRNA-mediated gene silencing contributes to neuronal development and brain vascularization via regulating its essential target genes. Specifically we will address 1) the functional role of Ago2 in excitatory neurons on neurogenesis, neuronal migration and differentiation; 2) the cellular metabolic regulation of Ago2 and its targeted miRNAs on neurons upon pathophysiological stress; and 3) how Ago2 in excitatory neurons regulates brain angiogenesis and vascularization. Furthermore, although Vgat-Cre, Ago2flox/flox mice did not show obviously pathological phenomenon until P16 and survive normally, it is still interest to investigate 4) the functional role of Ago2 in Vgat-expressing inhibitory neurons on neural circuit and mouse behavior. The findings of this project will extend our understanding of the functional role and mechanism of Ago2 and its associated miRNAs during brain development.