Abstract
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.
Highlights
Migration of neuroblasts and neurons is a key developmental process in the formation of neural circuits and networks
Fluorescent‐activated cell sorting of muscle cells and RNA seq myo-3::gfp-expressing body wall muscle cells from synchronized early L1 larvae were isolated by fluorescence activated cell sorting (FACS) as described in Material and Methods and in [42, 43] (Fig. 1)
We found that etr-1(lq61) affected unc-52 transcript expression in muscle cells. unc-52 was identified in both exon representation by DEXseq and transcript accumulation by DEseq2 (Table 2)
Summary
Migration of neuroblasts and neurons is a key developmental process in the formation of neural circuits and networks. The CELF (CUGBP, ELAV-like family) class of RNA-binding proteins is implicated in a wide variety of. Ochs et al BMC Genomics (2022) 23:13 an RRM organization conserved across CELF protein family members [16]. In C. elegans, there are two CELF genes, etr-1 (most similar to CELF1–2) [19, 20], and unc-75 (most similar to CELF3–6) [21]. Unc-75 controls alternative splicing events predominantly in the nervous system [21,22,23,24,25]. ETR-1 controls cell corpse engulfment in the germline [26], and influences neuronal migration non-autonomously from body wall muscle [20]
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