RIVERSIDE, Calif. -- 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."
The University of California, Riverside is a doctoral research university, a living laboratory for groundbreaking exploration of issues critical to Inland Southern California, the state and communities around the world. Reflecting California's diverse culture, UCR's enrollment is more than 26,000 students. The campus opened a medical school in 2013 and has reached the heart of the Coachella Valley by way of the UCR Palm Desert Center. The campus has an annual impact of more than $2.7 billion on the U.S. economy. To learn more, visit www.ucr.edu .
