TY  - JOUR
AU  - Sona, Chandan
AU  - Yeh, Yu-Te
AU  - Li, Yunxiao
AU  - Liu, Xiaoxuan
AU  - Ghosh, Adhideb
AU  - Hinte, Laura C
AU  - Ku, Min-Chi
AU  - Rathjen, Thomas
AU  - Niendorf, Thoralf
AU  - Yu, Guoxing
AU  - Jia, Shiqi
AU  - Kononenko, Natalia L
AU  - Hermann, Andreas
AU  - Luo, Jiankai
AU  - Lin, Juntang
AU  - von Meyenn, Ferdinand
AU  - Yan, Xin
AU  - Poy, Matthew N
TI  - Glutamatergic argonaute2 promotes the formation of the neurovascular unit in mice.
JO  - Science signaling
VL  - 18
IS  - 875
SN  - 1945-0877
CY  - Washington, DC [u.a.]
PB  - Assoc.
M1  - DZNE-2025-00378
SP  - eadl6745
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Argonaute Proteins: metabolism
KW  - Argonaute Proteins: genetics
KW  - PTEN Phosphohydrolase: metabolism
KW  - PTEN Phosphohydrolase: genetics
KW  - Mice
KW  - Humans
KW  - Neurons: metabolism
KW  - Reelin Protein
KW  - MicroRNAs: metabolism
KW  - MicroRNAs: genetics
KW  - Signal Transduction
KW  - Blood-Brain Barrier: metabolism
KW  - Proto-Oncogene Proteins c-akt: metabolism
KW  - Proto-Oncogene Proteins c-akt: genetics
KW  - Phosphatidylinositol 3-Kinases: metabolism
KW  - Phosphatidylinositol 3-Kinases: genetics
KW  - Mice, Knockout
KW  - Glutamic Acid: metabolism
KW  - Argonaute Proteins (NLM Chemicals)
KW  - PTEN Phosphohydrolase (NLM Chemicals)
KW  - Ago2 protein, mouse (NLM Chemicals)
KW  - Reln protein, mouse (NLM Chemicals)
KW  - Reelin Protein (NLM Chemicals)
KW  - RELN protein, human (NLM Chemicals)
KW  - Pten protein, mouse (NLM Chemicals)
KW  - MicroRNAs (NLM Chemicals)
KW  - Proto-Oncogene Proteins c-akt (NLM Chemicals)
KW  - Phosphatidylinositol 3-Kinases (NLM Chemicals)
KW  - AGO2 protein, human (NLM Chemicals)
KW  - Glutamic Acid (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39999211
DO  - DOI:10.1126/scisignal.adl6745
UR  - https://pub.dzne.de/record/277315
ER  -