Microexon in DAAM1 Protein Found Critical for Memory and Brain Function

Cells use a process called splicing to cut and rearrange gene messages, allowing a single gene to generate multiple proteins. This mechanism is especially active in the brain, where it provides the diversity needed for complex tissue and organ functions. Researchers at the Centre for Genomic Regulation (CRG) have identified a specific microexon, a short gene fragment just nine amino acids long, that is inserted into the DAAM1 protein only in neurons.

The inclusion of this microexon is essential for healthy neuronal development and impacts memory function. When the microexon was deleted in mice, the animals were born healthy, but as adults, their brain cells had about half the normal number of “learning spines,” structures necessary for forming new synaptic connections. This reduction led to a 40% decrease in memory performance in standard tests.

Patryk Poliński, first author of the study published in Nature Communications, explained, “The neurons look almost normal under the microscope, yet their ability to communicate and therefore process the information was strongly impacted. Neurons can’t build bridges as effectively, and the messengers can't do their job.” The team found that by chemically altering an overactive signaling pathway caused by the absence of the microexon, some neuronal firing and memory function could be restored. Co-senior author Mara Dierssen added, “Our work proves the brain’s ability to retrieve memories can recover when the right molecular switch is flipped.” However, the researchers caution that this is only proof of principle and not a therapy.

The importance of the microexon is underscored by its evolutionary conservation; the same sequence is present in sharks, indicating its critical role over hundreds of millions of years. Co-senior author Professor Manuel Irimia noted, “When the very same nine amino acids turn up in both sharks and humans, you’re looking at a molecular part so useful that evolution has refused to tinker with it for nearly half a billion years.” 

Previous work has shown that skipping neuron-specific microexons is common in autism spectrum disorder. The team is now searching for rare human variants missing the DAAM1 microexon and investigating other microexons that may influence cognition.