Summary: The seat of higher intelligence, the cerebral cortex, depends on neurons reaching precise locations to form organized layers. A new study identifies a critical RNA “surveillance system” called nonsense-mediated mRNA decay (NMD) as the architect behind this process.
Researchers found that a core NMD component, UPF2, is essential for neurons to move at the right speed and stop in their designated layers. Without it, the brain becomes disorganized and significantly smaller. This discovery provides a vital link between RNA regulation and neurodevelopmental disorders like epilepsy, autism, and schizophrenia.
Key Facts
- RNA Architect: NMD is not just a trash-collector for faulty RNA; it is a master regulator that orchestrates how neurons move during brain development.
- The UPF2 Switch: Deleting the UPF2 protein leads to slow-moving neurons that fail to reach their target layers, resulting in a disorganized cerebral cortex.
- Rescuing Size vs. Structure: By turning off the p53 protein, researchers could restore a normal brain size, but the disorganized layers remained, proving that UPF2 has a specific, independent role in guiding neurons.
- Molecular Sabotage: Without UPF2, the brain abnormally activates genes like Foxj1 and Ino80, which sabotage the Reelin signaling pathway—the “GPS” that neurons use to find their place.
- Ciliary Interference: Disrupted NMD causes young neurons to mistakenly activate a gene program for building hair-like cilia, which physically stops them from migrating properly.
Source: UCR
The cerebral cortex, the brain’s outermost region responsible for higher cognitive functions, depends on a highly ordered, layered structure. Its proper development requires newly generated neurons to migrate to precise locations at specific times.
Disruptions in neuronal migration or cortical lamination can lead to profound alterations in cortical circuitry, impairing synaptic connectivity and information processing — defects linked to a range of neurodevelopmental disorders, including epilepsy, intellectual disability, autism spectrum disorders, and schizophrenia.
New research from the School of Medicine at the University of California, Riverside, now identifies nonsense-mediated mRNA decay (NMD), a fundamental regulated RNA decay pathway, as a central mediator of this process.
The study, published in Cell Reports, shows that UPF2, a core component of the NMD machinery, is essential for proper neuronal migration and cortical lamination during brain development.
Sika Zheng, a professor of biomedical sciences who led the study, explained that NMD normally acts as a surveillance system that eliminates faulty or inappropriate RNA transcripts, preventing the production of incorrect proteins.
Although mutations in NMD-related genes have been linked to neurodevelopmental disorders, their specific role in shaping cortical structure remains unclear, he said.
“By selectively removing UPF2 from radial glial cells and their neuronal progenies, we observed defects in neuronal migration,” said Zheng, who directs the Center for RNA Biology and Medicine on campus.
“Neurons moved more slowly and some failed to reach their designated cortical layers. As a result, the normal laminar organization of the cortex was lost. In addition, we found brains lacking UPF2 were significantly smaller, indicating that the pathway also contributes to overall brain growth.”
Next, Zheng and his team turned off p53, a protein that normally slows down cell proliferation and makes damaged cells self-destruct. They found brain size returned to normal even without UPF2, showing that the small brain size was rescuable by removing p53.
“The layers of the brain, however, were still disorganized,” Zheng said. “This told us UPF2 isn’t just needed to develop a normal brain size; it also has a separate job helping neurons move to the right place during development.”
The team’s molecular analyses showed that loss of UPF2 lowered the expression of genes needed for neuron movement and positioning. These genes included parts of the Reelin signaling pathway, which guides migrating neurons, and genes that help build microtubules, the internal scaffolding cells use to move and transport cellular materials.
“This decrease in gene expression was partly caused by increased activity of Ino80, a protein that shuts down these movement-related genes,” Zheng said.
The researchers also found that disruption of NMD inappropriately activated a gene program — one normally used by cells that grow tiny hair-like structures called cilia. A gene called Foxj1, which drives cilia formation, became highly active. When the researchers artificially turned on Foxj1 in young brain cells, the neurons stopped migrating properly, just as they did when UPF2 was missing.
“Both Ino80 and Foxj1 are normally removed by NMD; without UPF2, both genes are abnormally upregulated,” Zheng said. “Our findings provide insights into how problems with NMD components like UPF2 can lead to neurodevelopmental disorders, where the brain’s internal structure is abnormal.”
Zheng was joined in the study by Lin Lin, Naoto Kubota, Yi-Li Lam, and Min Zhang at UCR; and Michelle Mingxue Song at the California University of Science and Medicine.
The study was funded by the National Institutes of Health.
The title of the paper is “Nonsense-mediated mRNA decay orchestrates neuronal migration and cortical lamination while modulating reelin and ciliary gene regulatory networks.”
Key Questions Answered:
A: Your brain relies on a strict, six-layer “zip code” system. If neurons don’t reach their designated layers, the electrical wiring of the brain becomes crossed. This “mis-wiring” is a primary driver of conditions like epilepsy, intellectual disabilities, and autism.
A: Scientists used to think so! But this study proves it’s more like a highly specialized traffic controller. By getting rid of “inappropriate” RNA, NMD ensures that only the right signals for movement and positioning are active. Without this controller, your neurons end up in a massive pile-up.
A: Yes. Now that we know UPF2 and the NMD pathway are the ones holding the map, researchers can look for ways to stabilize this surveillance system or target the specific “saboteur” genes that get turned on when the system fails.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this genetics and neuroscience research news
Author: Iqbal Pittalwala
Source: UCR
Contact: Iqbal Pittalwala – UCR
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Nonsense-mediated mRNA decay orchestrates neuronal migration and cortical lamination while modulating reelin and ciliary gene regulatory networks” by . Cell Reports
DOI:10.1016/j.celrep.2026.117027
Abstract
Nonsense-mediated mRNA decay orchestrates neuronal migration and cortical lamination while modulating reelin and ciliary gene regulatory networks
Nonsense-mediated mRNA decay (NMD) is associated with neurodevelopmental disorders, yet its role in cortical organization is unknown. We demonstrate that NMD mediated by UPF2 is indispensable for cortical organization.
Conditional deletion of Upf2 in radial glial cells delays neuronal migration and disrupts cortical lamination. Trp53 knockout rescues microcephaly from Upf2 deficiency but cannot rescue lamination defects, showing that UPF2’s role in neuronal migration is uncoupled from its regulation of cell cycle and independent of p53. UPF2 deficiency downregulates key neuronal migration genes in the Reelin signaling pathway and microtubule assembly (e.g., Dab1, Lrp8, Tubb2b, and Tuba1a), partly through upregulation of the transcriptional repressor Ino80. Additionally, NMD inhibition induces widespread upregulation of ciliary genes.
Ectopic expression of Foxj1, a master regulator of ciliary genes and an NMD target, impedes neuronal migration, phenocopying Upf2 loss. Therefore, NMD is a central post-transcriptional mechanism coordinating migration and ciliary gene networks crucial for cortical structure development.
