Summary: Researchers report they have uncovered a gene responsible for brain development and also discovered how it may work.
Source: UC Sant Barbara.
Neuroscience researchers identify a gene critical for human brain development and unravel how it works.
Compared to other mammals, humans have the largest cerebral cortex. A sheet of brain cells that folds in on itself multiple times in order to fit inside the skull, the cortex is the seat of higher functions. It is what enables us to process everything we see and hear and think.
The expansion of the cerebral cortex sets humans apart from the rest of their fellow primates. Yet scientists have long wondered what mechanisms are responsible for this evolutionary development.
New research from the Kosik Molecular and Cellular Neurobiology Lab at UC Santa Barbara has pinpointed a specific long nocoding ribonucleic acid (lncRNA) that regulates neural development (ND). The findings appear in the journal Neuron.
“This lncND, as we’ve called it, can be found only in the branch of primates that leads to humans. It is a stretch of nucleotides that does not code a protein,” said senior author Kenneth S. Kosik, the Harriman Professor of Neuroscience Research in UCSB’s Department of Molecular, Cellular, and Developmental Biology. “We demonstrate that lncND is turned on during development and turned off when the cell matures.”
Lead author Neha Rani, a postdoctoral scholar in the Kosik Lab, idenfitied several binding sites on lncND for another type of RNA called a microRNA. One of them, called microRNA-143, binds to lncND.
“We found that lncND could sequester this microRNA and in doing so regulate the expression of Notch proteins,” Rani said. “Notch proteins are very important regulators during neuronal development. They are involved in cell differentiation and cell fate and are critical in the neural development pathway.”
Kosik describes lncND as a platform that binds these microRNAs like a sponge. “This allows Notch to do what it’s supposed to do during development,” he explained. “Then as the brain matures, levels of lncND go down and when they do, those microRNAs come flying off the platform and glom onto Notch to bring its levels down. You want Notch levels to be high while the brain is developing but not once maturation occurs. This lncND is an elegant way to change Notch levels quickly.”
To replicate these cell culture results, Rani used human stem cells to grow neurons into what is called a mini brain. In this pea-sized gob of brain tissue, she identified a subpopulation — radial glial cells (neuronal stem cells) and other neural progenitors — responsible for making lncND.
But the researchers wanted to see the radial glial cells in actual human brain tissue, so they turned to colleagues in the Developmental & Stem Cell Biology Graduate Program at the UC San Francisco School of Medicine. Using in situ hybridization, UCSF scientists found lncND in neural precursor cells but not in mature neurons.
“It was right where we thought it would be in brain tissue,” said Kosik, who is also the co-director of UCSB’s Neuroscience Research Institute. “But we still had one more thing we had to do because people would still not be satisfied that we had done everything possible to show that lncND was really doing something functionally.”
So the UCSF team introduced lncND into the fetal brain of a gestating mouse. Green fluorescent protein labeling allowed them to see the early development pattern and show that lncND, which ordinarily is not present in mice — lncND is present only in some primates including humans — had a functional effect on development.
“When we overexpressed lncND in the mouse fetus, we actually affected development in the predicted manner,” Kosik said. “The early developmental pattern was shifted toward more precursor cells, even though the mouse does not make lncND at all.”
According to Kosik, this work not only identifies a very critical gene for human brain development but also offers a clue about a component that likely contributed to brain expansion in humans. “We have shown that lncND might be an important player in human brain expansion, which is exciting in itself,” Rani said. “Another interesting aspect of this work is that lncND appears to help regulate the key developmental pathway of Notch signaling.”
Funding: This work was supported in part by Mathematics of Information Technology and Complex Systems (MITACS, Grant #IT03240), National Sciences and Engineering Council Canada (NSERC, Grant #298457-2009), and Canadian Institutes for Health Research (CIHR, Grant #CCI-109608).
Conflict of Interest: Several of the authors are associated with HealthTech Connex Inc. which may qualify them to financially benefit from the commercialization of a NeuroCatch™ platform capable of measuring brain vital signs.
Source: Julie Cohen – UC Sant Barbara
Image Source: This NeuroscienceNews.com image is credited to Neha Rani.
Original Research: Abstract for “A Primate lncRNA Mediates Notch Signaling during Neuronal Development by Sequestering miRNA” by Neha Rani, Tomasz J. Nowakowski, Hongjun Zhou, Sirie E. Godshalk, Véronique Lisi, Arnold R. Kriegstein, and Kenneth S. Kosik in Neuron. Published online June 2 2026 doi:10.1016/j.neuron.2016.05.005
A Primate lncRNA Mediates Notch Signaling during Neuronal Development by Sequestering miRNA
•Identification of LncND with a Catarrhine insertion of 16 MREs for miR-143-3p
•LncND regulates expression of Notch genes by sequestering miR-143-3p
•High expression of LncND in radial glia cells in human VZ and OSVZ
•LncND appears to be involved in the expansion of radial glia cells in primates
Long non-coding RNAs (lncRNAs) are a diverse and poorly conserved category of transcripts that have expanded greatly in primates, particularly in the brain. We identified an lncRNA, which has acquired 16 microRNA response elements for miR-143-3p in the Catarrhini branch of primates. This lncRNA, termed LncND (neurodevelopment), is expressed in neural progenitor cells and then declines in neurons. Binding and release of miR-143-3p by LncND control the expression of Notch receptors. LncND expression is enriched in radial glia cells (RGCs) in the ventricular and subventricular zones of developing human brain. Downregulation in neuroblastoma cells reduced cell proliferation and induced neuronal differentiation, an effect phenocopied by miR-143-3p overexpression. Gain of function of LncND in developing mouse cortex led to an expansion of PAX6+ RGCs. These findings support a role for LncND in miRNA-mediated regulation of Notch signaling within the neural progenitor pool in primates that may have contributed to the expansion of cerebral cortex.
“A Primate lncRNA Mediates Notch Signaling during Neuronal Development by Sequestering miRNA” by Neha Rani, Tomasz J. Nowakowski, Hongjun Zhou, Sirie E. Godshalk, Véronique Lisi, Arnold R. Kriegstein, and Kenneth S. Kosik in Neuron. Published online June 2 2026 doi:10.1016/j.neuron.2016.05.005