MBL-1 and EEL-1 affect the splicing and protein levels of MEC-3 to control dendrite complexity

Abstract

<jats:p>Transcription factors (TFs) play critical roles in specifying many aspects of neuronal cell fate including dendritic morphology. How TFs are accurately regulated during neuronal morphogenesis is not fully understood. Here, we show that LIM homeodomain protein MEC-3, the key TF for <jats:italic>C</jats:italic>. <jats:italic>elegans</jats:italic> PVD dendrite morphogenesis, is regulated by both alternative splicing and an E3 ubiquitin ligase. The <jats:italic>mec-3</jats:italic> gene generates several transcripts by alternative splicing. We find that <jats:italic>mbl-1</jats:italic>, the orthologue of the muscular dystrophy disease gene muscleblind-like (MBNL), is required for PVD dendrite arbor formation. Our data suggest <jats:italic>mbl-1</jats:italic> regulates the alternative splicing of <jats:italic>mec-3</jats:italic> to produce its long isoform. Deleting the long isoform of <jats:italic>mec-3(deExon2)</jats:italic> causes reduction of dendrite complexity. Through a genetic modifier screen, we find that mutation in the E3 ubiquitin ligase EEL-1 suppresses <jats:italic>mbl-1</jats:italic> phenotype. <jats:italic>eel-1</jats:italic> mutants also suppress <jats:italic>mec-3(deExon2)</jats:italic> mutant but not the <jats:italic>mec-3</jats:italic> null phenotype. Loss of EEL-1 alone leads to excessive dendrite branches. Together, these results indicate that MEC-3 is fine-tuned by alternative splicing and the ubiquitin system to produce the optimal level of dendrite branches.</jats:p>