PUBLICATION
Phenotypic impact of individual conserved neuronal microexons and their master regulators in zebrafish
- Authors
- Lopez-Blanch, L., Rodríguez-Marin, C., Mantica, F., Iñiguez, L.P., Permanyer, J., Kita, E.M., Mackensen, T., Codina-Tobias, M., Romero-Ferrero, F., Fernandez-Albert, J., Cuadrado, M., Bustelo, X.R., de Polavieja, G., Irimia, M.
- ID
- ZDB-PUB-251119-4
- Date
- 2025
- Source
- eLIFE 13: (Journal)
- Registered Authors
- Irimia, Manuel, Permanyer, Jon
- Keywords
- compensation, genetics, genomics, master regulators, microexons, zebrafish
- MeSH Terms
-
- Animals
- Neurons*/metabolism
- Neurons*/physiology
- Social Behavior
- Exons*
- Zebrafish*/genetics
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Phenotype
- Locomotion
- RNA Splicing Factors*/genetics
- RNA Splicing Factors*/metabolism
- Neurogenesis/genetics
- PubMed
- 41252189 Full text @ Elife
Citation
Lopez-Blanch, L., Rodríguez-Marin, C., Mantica, F., Iñiguez, L.P., Permanyer, J., Kita, E.M., Mackensen, T., Codina-Tobias, M., Romero-Ferrero, F., Fernandez-Albert, J., Cuadrado, M., Bustelo, X.R., de Polavieja, G., Irimia, M. (2025) Phenotypic impact of individual conserved neuronal microexons and their master regulators in zebrafish. eLIFE. 13:.
Abstract
Microexons exhibit striking evolutionary conservation and are subject to precise, switch-like regulation in neurons, orchestrated by the splicing factors Srrm3 and Srrm4. Disruption of these regulators in mice leads to severe neurological phenotypes, and their misregulation is linked to human disease. However, the specific microexons involved in these phenotypes and the effects of individual microexon deletions on neurodevelopment, physiology, and behavior remain poorly understood. To explore this, we generated zebrafish lines with deletions of 18 individual microexons, alongside srrm3 and srrm4 mutant lines, and conducted comprehensive phenotypic analyses. We discovered that while loss of srrm3, alone or together with srrm4, resulted in significant alterations in neuritogenesis, locomotion, and social behavior, individual microexon deletions typically produced mild or no noticeable effects. Nonetheless, we identified specific microexons associated with defects in neuritogenesis (evi5b, vav2, itsn1, src) and social behavior (vti1a, kif1b). Additionally, most microexon deletions triggered coordinated transcriptomic changes in neural pathways, suggesting the presence of molecular compensatory mechanisms. Our findings suggest that the severe phenotypes caused by Srrm3/4 depletion arise from the combined effects of multiple subtle disruptions across various cellular pathways, which are individually well-tolerated.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping