ARTICLE: Glutamatergic argonaute2 promotes the formation of the neurovascular unit in mice
AUTHORS: Chandan Sona, Yu-Te Yeh, Yunxiao Li, Xiaoxuan Liu, Adhideb Ghosh, Laura C Hinte, Min-Chi Ku, Thomas Rathjen, Thoralf Niendorf, Guoxing Yu, Shiqi Jia, Natalia L Kononenko, Andreas Hermann, Jiankai Luo, Juntang Lin, Ferdinand von Meyenn, Xin Yan, Matthew N Poy
JOURNAL: ci Signal. 2025 Feb 25;18(875):eadl6745. doi: 10.1126/scisignal.adl6745. Epub 2025 Feb 25.
Abstract
Proper formation of the complex neurovascular unit (NVU) along with the blood-brain barrier is critical for building and sustaining a healthy, functioning central nervous system. The RNA binding protein argonaute2 (Ago2) mediates microRNA (miRNA)-mediated gene silencing, which is critical for many facets of brain development, including NVU development. Here, we found that Ago2 in glutamatergic neurons was critical for NVU formation in the developing cortices of mice. Glutamatergic neuron-specific loss of Ago2 diminished synaptic formation, neuronal-to-endothelial cell contacts, and morphogenesis of the brain vasculature, ultimately compromising the integrity of the blood-brain barrier. Ago2 facilitated miRNA targeting of phosphatase and tensin homolog (Pten) mRNA, which encodes a phosphatase that modulates reelin-dependent phosphatidylinositol 3-kinase (PI3K)-Akt signaling within the glutamatergic subpopulation. Conditionally deleting Pten in Ago2-deficient neurons restored Akt2 phosphorylation as well as postnatal development and survival. Several mutations in AGO2 impair small RNA silencing and are associated with Lessel-Kreienkamp syndrome, a neurodevelopmental disorder. When expressed in a neuronal cell line, these human AGO2 loss-of-function variants failed to suppress PTEN, resulting in attenuated PI3K-Akt signaling, further indicating that dysregulation of Ago2 function may contribute to both impaired development and neurological disorders. Together, these results identify Ago2 as central to the engagement of neurons with blood vessels in the developing brain.
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