Remote Signals Can Change Neuronal Fate, Offering a New Key to Brain Development

A study has found that remote signals in the brain can directly change neuronal “fate.” Inputs from the thalamus determine not only cortical maturation but also which cell types neural progenitor cells differentiate into.

On the 3rd (local time), a research team led by Aparna Bhaduri at the University of California, Los Angeles (UCLA), published a paper reporting these findings in the international journal Science.

Excitatory neurons in the outer layers of the human cerebral cortex are produced mainly by a specialized neural progenitor cell called the outer radial glia (oRG). The proliferative and differentiation capacity of oRG cells has been considered central to the evolution of the human cortex.

The researchers fused human stem cell-derived cortical organoids with thalamic organoids to recreate early innervation. They found that thalamic input substantially increased the production of upper-layer neurons, including SATB2-, CUX1- and BRN2-expressing cells, alongside dynamic changes in HOPX-positive oRG cells and increased neurogenic output.

Experiments separating the timing of inputs identified a “critical period” during which early thalamic input alone could alter cortical developmental trajectories over the long term. Lineage tracing showed that thalamic signals directed oRG cells toward neurogenesis rather than self-renewal.

The researchers also identified a molecular link: neurexin 1 (NRXN1) in thalamic neurons and neuroligin 1 (NLGN1) in cortical oRG cells mediate physical contact. Super-resolution imaging confirmed direct contact based on the two molecules in the outer subventricular zone of the human cortex during midgestation.

When the team used CRISPR to remove NRXN1 from thalamic organoids, cell-to-cell contact decreased, as did the production of oRG cells and upper-layer neurons. Radial glia increased, while gene programs shifted away from neurogenic maturation.

The study is the first to show that long-range projections between brain regions are not simply “wiring” but directly contribute to neural progenitor cell fate decisions through physical contact. It broadens understanding of human cortical development from “cortical autonomy” to “cooperation between brain regions.”

The researchers noted, however, that organoid models lack blood vessels and an immune microenvironment, and that quantitative differences between the fusion system and the effects of the thalamus in the actual brain should be interpreted cautiously. Even so, the findings are expected to provide a new platform for studying the disease mechanisms of NRXN1 mutations in autism spectrum disorder.