Summary: Circular RNAs (circRNAs) are stable, closed-loop RNA molecules that play important roles in brain development, synaptic function, and long-term cellular regulation. Their circular form protects them from degradation, making them especially well suited to neurons. New research from the Max Planck Institute has identified the RNA-binding protein ELAV as a global regulator that shifts RNA processing toward circRNA production by slowing linear splicing and promoting back-splicing. These findings, discovered in Drosophila embryos, point to a conserved mechanism that may also operate in the human brain and could open new avenues for studying brain health and neurodegenerative disease.
Circular RNAs are produced by back-splicing of precursor messenger RNAs (pre-mRNAs), a process that joins a downstream splice donor to an upstream splice acceptor to create a covalently closed loop. Although circRNAs are expressed across species and in many tissues, they accumulate particularly strongly in neurons. Their abundance in the nervous system and their potential regulatory roles—ranging from modulation of gene expression to acting as molecular sponges or templates for translation—have made them a focus of growing interest in neuroscience and genetics.
- Stability advantage: The closed-loop structure of circRNAs lacks free ends, rendering them resistant to exonucleases and enabling long-term stability in non-dividing cells such as neurons.
- Regulatory switch: The ELAV protein acts as a master regulator, favoring back-splicing over canonical linear splicing and thereby promoting widespread circRNA formation in neurons.
- Clinical relevance: ELAV-like proteins are conserved across species, raising the possibility that manipulating this pathway could affect circRNA levels in the human brain and inform research into neurodevelopmental and neurodegenerative disorders.
Researchers at the Max Planck Institute for Immunobiology and Epigenetics in Freiburg mapped circRNA expression during Drosophila embryonic neural development and examined how loss or gain of the protein ELAV affects circRNA levels. ELAV is a pan-neuronal RNA-binding protein previously implicated in multiple aspects of RNA metabolism. The new work shows that ELAV directly influences the balance between linear splicing and back-splicing, acting as a decisive factor for the neuronal circRNA landscape.
A stable ring with significant functions
CircRNAs’ resistance to degradation stems from their circular topology: without free 5′ or 3′ ends, they evade exonuclease-driven decay and can persist in the cell for extended periods. This durability makes them well suited for sustained regulatory roles in neurons, where long-term maintenance of RNA-mediated processes is essential for synaptic plasticity and memory. Experimental evidence suggests that circRNAs can modulate gene expression, sequester microRNAs or RNA-binding proteins, and in some cases serve as templates for protein production.
“These RNAs can control gene activity and interact with other regulators; understanding how cells generate them is key to decoding their functions,” says Mengjin Shi, a lead author on the study.
ELAV as a master switch for circRNA production
The study demonstrated that removing ELAV from developing fruit fly neurons causes a dramatic global drop in circRNA levels—by more than 75%—while ectopic expression of ELAV in cells that normally make few circRNAs is sufficient to induce circularization. Mechanistically, ELAV binds to intronic regions of pre-mRNAs that flank circRNA-producing exons. By associating with these introns, ELAV slows the conventional linear splicing pathway and promotes intron pairing through reverse-complementary sequences, a configuration that favors back-splicing and loop formation.
Put simply, ELAV’s binding brings the ends of a nascent circRNA into proximity and reduces the speed or efficiency of canonical splicing, thereby biasing the splicing machinery toward circularization. The authors argue that neuronal circRNAs are not accidental byproducts but are deliberately produced through regulated splicing decisions to serve functional roles in the nervous system.
Valérie Hilgers, senior author of the study, highlights the broader implications: because ELAV-like proteins exist in mammals, an analogous mechanism likely contributes to circRNA biogenesis in the human brain. If so, targeted modulation of ELAV family proteins could provide a tool to adjust circRNA levels experimentally and potentially reveal roles for circRNAs in neurodevelopmental processes, synaptic function, and neurodegeneration.
Research context and authorship
Author: Marcus Rockoff
Source: Max Planck Institute
Contact: Marcus Rockoff – Max Planck Institute
Image: The image is credited to Neuroscience News
Original Research: Open access. “ELAV mediates circular RNA biogenesis in neurons” by Mengjin Shi et al., published in Genes & Development. The study reports that ELAV binds pre-mRNA introns flanking putative circRNAs, diminishes linear splicing efficiency, and promotes intron pairing and back-splicing to generate neuronal circRNAs.
Abstract (condensed)
Circular RNAs arise from back-splicing of precursor RNAs and accumulate in animal nervous systems, where they are implicated in gene regulation and synaptic function. This study shows that neuronal circRNA biosynthesis is mediated by the pan-neuronal RNA-binding protein ELAV. In Drosophila embryos, ELAV loss leads to a global depletion (>75%) of neuronal circRNAs, while ELAV expression induces ectopic circularization. ELAV binds introns flanking putative circRNAs and decreases linear splicing efficiency in favor of intron pairing and back-splicing, directly modulating splicing decisions to shape the neuronal circRNA landscape.