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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>","DOI":"10.1371\/journal.pgen.1010941","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T17:25:55Z","timestamp":1695230755000},"page":"e1010941","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["MBL-1 and EEL-1 affect the splicing and protein levels of MEC-3 to control dendrite 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