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@ARTICLE{Sona:277315,
author = {Sona, Chandan and Yeh, Yu-Te and Li, Yunxiao and Liu,
Xiaoxuan and Ghosh, Adhideb and Hinte, Laura C and Ku,
Min-Chi and Rathjen, Thomas and Niendorf, Thoralf and Yu,
Guoxing and Jia, Shiqi and Kononenko, Natalia L and Hermann,
Andreas and Luo, Jiankai and Lin, Juntang and von Meyenn,
Ferdinand and Yan, Xin and Poy, Matthew N},
title = {{G}lutamatergic argonaute2 promotes the formation of the
neurovascular unit in mice.},
journal = {Science signaling},
volume = {18},
number = {875},
issn = {1945-0877},
address = {Washington, DC [u.a.]},
publisher = {Assoc.},
reportid = {DZNE-2025-00378},
pages = {eadl6745},
year = {2025},
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.},
keywords = {Animals / Argonaute Proteins: metabolism / Argonaute
Proteins: genetics / PTEN Phosphohydrolase: metabolism /
PTEN Phosphohydrolase: genetics / Mice / Humans / Neurons:
metabolism / Reelin Protein / MicroRNAs: metabolism /
MicroRNAs: genetics / Signal Transduction / Blood-Brain
Barrier: metabolism / Proto-Oncogene Proteins c-akt:
metabolism / Proto-Oncogene Proteins c-akt: genetics /
Phosphatidylinositol 3-Kinases: metabolism /
Phosphatidylinositol 3-Kinases: genetics / Mice, Knockout /
Glutamic Acid: metabolism / Argonaute Proteins (NLM
Chemicals) / PTEN Phosphohydrolase (NLM Chemicals) / Ago2
protein, mouse (NLM Chemicals) / Reln protein, mouse (NLM
Chemicals) / Reelin Protein (NLM Chemicals) / RELN protein,
human (NLM Chemicals) / Pten protein, mouse (NLM Chemicals)
/ MicroRNAs (NLM Chemicals) / Proto-Oncogene Proteins c-akt
(NLM Chemicals) / Phosphatidylinositol 3-Kinases (NLM
Chemicals) / AGO2 protein, human (NLM Chemicals) / Glutamic
Acid (NLM Chemicals)},
cin = {AG Hermann},
ddc = {500},
cid = {I:(DE-2719)1511100},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39999211},
doi = {10.1126/scisignal.adl6745},
url = {https://pub.dzne.de/record/277315},
}