New study shows that mice losing AGO1 show key features of autism spectrum disorder
Study title: AGO1 in neural progenitor cells orchestrates brain development and sociability via the LIN28A-REELIN axis
This study by the Han lab shows that the AGO1 gene plays a crucial role in early brain development—especially in how brain cells organise themselves—and that losing AGO1 disrupts sociability, brain structure, and key developmental pathways.
Pre-print Disclaimer
This study was shared on bioRxiv, which means it is a pre-print. Pre-prints have not yet been peer-reviewed by independent experts. This means the findings are preliminary.
Quick Explainers
KO mice or KO cells (Knockout): “KO” means knockout. This is when scientists deliberately switch off (“knock out”) a gene in an animal or in cells grown in the lab.
KO mice: mice in which a specific gene has been turned off.
KO cells: cells grown in a dish where that gene has been disabled. This helps researchers understand what the gene normally does.
Forebrain: The forebrain is the front and largest part of the brain. It develops very early in pregnancy and eventually forms major structures responsible for thinking, memory, emotions, and social behaviour. Forebrain “organoids” are miniature, early-stage models of this region grown from stem cells in the lab.
Neural progenitor cells (NPCs): NPCs are early brain-building cells. They appear very early in development and can divide and mature into different types of brain cells, including neurons. NPCs act like the construction crew of the developing brain: they organise themselves into layers and help shape brain structure.
What did the researchers find?
1. Removing AGO1 in the mouse brain reduces sociability
The team deleted AGO1 specifically in the developing mouse brain.
Mice without AGO1 behaved normally when exploring an open space.
But when meeting an unfamiliar mouse, they spent less time sniffing and interacting.
This reduced social engagement mimics one of the core behavioural features seen in autism spectrum disorders.
Do et al. BioRxiv. AGO1 KO mice spent less time sniffing
2. AGO1 knockout disrupts brain organoid development
Researchers then used human stem cells to create forebrain organoids—miniaturised, lab-grown early brain structures.
When AGO1 was removed, the researchers observed structural problems, that mirror abnormalities reported in the developing cortex of autistic individuals.
3. AGO1 loss impairs cell organisation and neuronal maturation
To pinpoint the cause of these organoid defects, the team grew neural progenitor cells (NPCs) and neurons in 2D culture.
They found that losing AGO1 did not change:
The number of NPCs,
Their ability to divide, or
Their ability to become neurons.
But it did disrupt how NPCs organise themselves:
Neural “rosettes” (ring-like structures that mimic early brain tubes) became misshapen.
The apical junctions (where cells attach to each other) were abnormal.
In neurons, AGO1 loss caused:
Shorter and fewer neurites (branches),
Fewer electrical spikes and bursts, showing weaker neural network activity.
This means that although cells form, they don’t mature or connect properly.
4. Fixing LIN28A or REELIN rescues the cellular defects
AGO1 suppresses a gene called LIN28A. When AGO1 was removed, LIN28A shot up. This in turn reduced REELIN, which is essential for organising neurons during development and is strongly linked to ASD.
The team tried two rescue strategies in AGO1-KO neural rosettes:
Reducing LIN28A
Adding recombinant human REELIN protein
Both approaches restored the tangled, oval-shaped rosettes back to normal round structures, meaning the tissue regained proper polarity and organisation.
In summary
This study shows that AGO1 is essential for the organisation of early brain tissue and the development of healthy neuronal networks. When AGO1 is missing:
Social behaviour in mice is reduced.
Early brain structures in organoids become disorganised.
Neural progenitors lose their polarity, and neurons do not mature well.
The underlying cause is an imbalance in the LIN28A–REELIN pathway: AGO1 normally keeps LIN28A low, allowing REELIN to support proper brain layering and neuronal development.
Why is this research relevant for AGO1 point mutations (often gain-of-function)?
Loss-of-function studies reveal the core “job” of AGO1 in the developing brain. Before understanding what a mutation changes, scientists must know what the normal protein does. If a mutation changes AGO1’s activity, it can still disrupt the same pathways, just in a different direction.
Gain- and loss-of-function often disturb the same biological pathway—but differently. This paper maps the pathways where problems appear.
Knowing the pathway helps identify therapeutic entry points—even if direction is reversed
Reveals possible therapeutic levers (LIN28A and REELIN)
