Caenorhabditis elegans ETR-1/CELF has broad effects on the muscle cell transcriptome, including genes that regulate translation and neuroblast migration

• Published in: BMC genomics Vol. 23; no. 1; p. 13
• Main Authors: Ochs, Matthew E, McWhirter, Rebecca M, Unckless, Robert L, Miller, 3rd, David M, Lundquist, Erik A
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 06-01-2022; BioMed Central; BMC
• Subjects: Alternative Splicing; Alzheimer's disease; Animals; Body wall; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Cardiomyocytes; Cell migration; Differentiation; Exons; Flow cytometry; Fluorescence; Functional analysis; Genes; Genetic aspects; Genomes; Genomics; Homology; Isoforms; Kinases; Muscle cells; Muscle Cells - metabolism; Muscle, Skeletal - metabolism; Muscles; Mutation; Neural circuitry; Neural networks; Neuroblasts; Neuromuscular diseases; Neurons; Perlecan; Physiological aspects; Physiology; Proteins; Ribonucleic acid; RNA; RNA processing; RNA-Binding Proteins - metabolism; Splicing; Stop codon; Transcription; Transcription factors; Transcriptome; Transcriptomes; Translation; Tropomyosin; Vertebrates; Wnt protein; United States
• ISSN: 1471-2164; 1471-2164
• DOI: 10.1186/s12864-021-08217-6

Migration of neuroblasts and neurons from their birthplace is central to the formation of neural circuits and networks. ETR-1 is the Caenorhabditis elegans homolog of the CELF1 (CUGBP, ELAV-like family 1) RNA-processing factor involved in neuromuscular disorders. etr-1 regulates body wall muscle differentiation. Our previous work showed that etr-1 in muscle has a non-autonomous role in neuronal migration, suggesting that ETR-1 is involved in the production of a signal emanating from body wall muscle that controls neuroblast migration and that interacts with Wnt signaling. etr-1 is extensively alternatively-spliced, and we identified the viable etr-1(lq61) mutant, caused by a stop codon in alternatively-spliced exon 8 and only affecting etr-1 isoforms containing exon 8. We took advantage of viable etr-1(lq61) to identify potential RNA targets of ETR-1 in body wall muscle using a combination of fluorescence activated cell sorting (FACS) of body wall muscles from wild-type and etr-1(lq61) and subsequent RNA-seq. This analysis revealed genes whose splicing and transcript levels were controlled by ETR-1 exon 8 isoforms, and represented a broad spectrum of genes involved in muscle differentiation, myofilament lattice structure, and physiology. Genes with transcripts underrepresented in etr-1(lq61) included those involved in ribosome function and translation, similar to potential CELF1 targets identified in chick cardiomyocytes. This suggests that at least some targets of ETR-1 might be conserved in vertebrates, and that ETR-1 might generally stimulate translation in muscles. As proof-of-principle, a functional analysis of a subset of ETR-1 targets revealed genes involved in AQR and PQR neuronal migration. One such gene, lev-11/tropomyosin, requires ETR-1 for alternative splicing, and another, unc-52/perlecan, requires ETR-1 for the production of long isoforms containing 3' exons. In sum, these studies identified gene targets of ETR-1/CELF1 in muscles, which included genes involved in muscle development and physiology, and genes with novel roles in neuronal migration.