Argonaute2 in excitatory neurons functionally regulates cellular metabolism and cerebral vascularization during brain development
Final Report Abstract
The current project investigated the function of Argonaute2 (Ago2), a key mediator of the microRNA (miRNA) pathway, in the specific neuronal populations of the brain during mouse postnatal development. The analysis of a series of genetic mouse lines established Ago2 as a regulator of neuron proliferation and differentiation by targeting multiple genes, e.g., Pten and Cadm1. Loss of Ago2 in excitatory neurons diminished synaptic formation, neuronal and endothelial cell contacts, and morphogenesis of the brain vasculature ultimately compromising the integrity of the blood brain barrier in the developing cortex. Mechanistic analysis indicated that Ago2 facilitated miRNA targeting of Pten, which regulated Reelin-dependent PI3K/Akt signaling in the glutamatergic subpopulation. Reversing the de-repression of Pten in Ago2-deficient neurons restored phosphorylation of Akt2, postnatal cortical development, and mouse survival. Moreover, over-expression AGO2, but not its mutant variants, strongly suppressed PTEN expression, indicating its dysregulation may contribute to human neurological disorders. Finally, the role of Ago2 in the developing retina was further examined and data showed that Ago2 loss in Vglut2-postive neurons affected retina ganglion cells growth, induced retinal morphological alterations, and impaired retinal vascularization. Taken together, our results indicate neuronal Ago2 function as a critical regulator of neuronal signaling pathways and illustrate that miRNA function is central to the engagement of neurons with blood vessels of the developing brain. Our observations functionally associating Ago2 together with miRNA-29 (miR-29) and Pten now identify a network within the miRNA pathway that coordinately regulates the brain development.
Publications
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The first International Argonaute Syndrome conference. Aug. 24-27, 2022 in Regensburg, Germany with abstract titled: Neuronal Argonaute2 is essential for brain development.
Jiankai Luo & Xin Yan
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The Argonaute 2024. Aug. 21-24, 2024 in Copenhagen, Denmark with abstract titled: Glutamatergic Argonaute2 controls retina development.
Yunxiao Li
