RIVERSIDE, Calif. — The cerebral cortex, the brain’s outermost region responsible for higher cognitive functions, relies on a highly ordered, layered structure. This critical formation requires newly generated neurons to migrate accurately to specific locations at precise times. Disruptions in this process can lead to significant alterations in cortical circuitry, impairing synaptic connectivity and information processing. Such defects are 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, 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, highlights the essential role of UPF2, a core component of the NMD machinery, in ensuring proper neuronal migration and cortical lamination during brain development.
The Role of NMD in Brain Development
Sika Zheng, a professor of biomedical sciences who led the study, explained that NMD acts as a surveillance system, eliminating faulty or inappropriate RNA transcripts to prevent the production of incorrect proteins. Although mutations in NMD-related genes have been linked to neurodevelopmental disorders, their specific role in shaping cortical structure had remained unclear until now.
“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.”
The announcement comes as researchers continue to explore the intricate processes underlying brain development. Zheng and his team further investigated by turning off p53, a protein that typically slows down cell proliferation and induces self-destruction in damaged cells. Remarkably, brain size returned to normal even without UPF2, demonstrating that the small brain size was rescuable by removing p53.
Unraveling the Complexity of Neuronal Migration
Despite the restoration of brain size, the layers of the brain remained disorganized, underscoring UPF2’s unique role in aiding neuron placement during development. The team’s molecular analyses revealed that the loss of UPF2 reduced the expression of genes essential for neuron movement and positioning. These genes are part of the Reelin signaling pathway, which guides migrating neurons, and include those involved in constructing microtubules, the internal scaffolding cells use for movement and material transport.
“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 discovered that disruption of NMD inappropriately activated a gene program typically used by cells to grow tiny hair-like structures called cilia. A gene known as Foxj1, which drives cilia formation, became highly active. When the researchers artificially activated Foxj1 in young brain cells, the neurons stopped migrating properly, mirroring the effects observed when UPF2 was absent.
“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.”
Implications for Neurodevelopmental Disorders
This development follows a growing body of research that seeks to understand the genetic and molecular underpinnings of neurodevelopmental disorders. The study’s findings could pave the way for new therapeutic approaches targeting NMD pathways to correct or mitigate the effects of these disorders.
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 exceeds 26,000 students. The campus opened a medical school in 2013 and has reached the heart of the Coachella Valley through 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.
