Glutamatergic argonaute2 promotes the formation of the neurovascular unit in mice

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Item Type:	Article
Title:	Glutamatergic argonaute2 promotes the formation of the neurovascular unit in mice
Creators Name:	Sona, C., Yeh, Y.T., Li, Y., Liu, X., Ghosh, A., Hinte, L.C., Ku, M.C., Rathjen, T., Niendorf, T., Yu, G., Jia, S., Kononenko, N.L., Hermann, A., Luo, J., Lin, J., von Meyenn, F., Yan, X. and Poy, M.N.
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 in glutamatergic neurons was critical for NVU formation in the developing cortices of mice. Glutamatergic neuron-specific loss of 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 () mRNA, which encodes a phosphatase that modulates reelin-dependent phosphatidylinositol 3-kinase (PI3K)-Akt signaling within the glutamatergic subpopulation. Conditionally deleting in -deficient neurons restored Akt2 phosphorylation as well as postnatal development and survival. Several mutations in impair small RNA silencing and are associated with Lessel-Kreienkamp syndrome, a neurodevelopmental disorder. When expressed in a neuronal cell line, these human 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.
Keywords:	Argonaute Proteins, Blood-Brain Barrier, Glutamic Acid, Knockout Mice, MicroRNAs, Neurons, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Reelin Protein, Signal Transduction, Animals, Mice
Source:	Science Signaling
ISSN:	1945-0877
Publisher:	American Association for the Advancement of Science
Volume:	18
Number:	875
Page Range:	eadl6745
Date:	25 February 2025
Official Publication:	https://doi.org/10.1126/scisignal.adl6745
PubMed:	View item in PubMed

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