The role of ETR-1/CELF1, an RNA binding protein, in Neuronal Migration

University Of Kansas Lawrence, Lawrence KS

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Abstract

The guided migration of neurons and neuronal progenitors in the nervous systems is a complex process involving extracellular cues that act through specific receptors and downstream signals to direct cell movements. The two bilateral Q neuroblasts in C. elegans offer a simple and genetically accessible model of neuronal progenitor migration. Despite identical differentiation patterns, QR on the right migrates anteriorly, whereas QL on the left moves toward the posterior. Thus, the Q cells express a shared program of differentiation but offer opposite responses to signals that direct cell migration. This proposal is designed to dissect a novel role of the CELF1 (CUG binding protein, Elav Family 1) molecule ETR-1 in Q neuroblast migration in C. elegans. CELF1 molecules are RNA-binding proteins that mediate multiple aspects of RNA processing, including alternative splicing. In an unbiased forward genetic screen for new mutations with defects in Q neuroblast migration, we identified a novel allele of etr-1, which encodes the C. elegans version of CELF1. Previous studies showed that etr-1 loss-of-function results in embryonic lethality with severe muscle disorganization, including defects in muscle attachment. The etr-1(lq61) mutation that we identified is viable, and corresponds to a premature stop codon in an alternatively-spliced exon that is limited to a subset of etr-1 transcripts. Thus, etr-1(lq61) offers a unique opportunity to probe the function of etr-1/CELF1 and the regulation of alternative mRNA processing in both muscle cell development and Q neuroblast migration. etr-1 expression in C. elegans is limited to body wall muscles. This observation suggests that etr-1 may exert an indirect effect on Q neuroblast migration, possibly via a secreted or transmembrane factor expressed from adjacent muscle cells. Indeed, preliminary results indicate that etr-1 acts in muscles in Q migrations. Q-cell migration is highly dependent on body muscle-derived Wnt signals. It is possible, for example, that etr-1 could regulate expression of a key component of the Wnt secretory pathway. On the other hand, additional aspects of Q cell migration do not require Wnt and are therefore likely to depend on alternative extracellular cues. The existence of a diverse set of transmembrane proteins that function in Q cells to regulate their migration, (e.g., UNC-40/DCC, PTP-3/LAR, MIG-21, MIG-13) (3, 4), underscores the importance of these additional intercellular signals to Q-cell trajectory. We hypothesize that ETR-1/CELF-1 regulates expression of key signals that are produced in muscle cells to guide Q neuroblast migration. In aim 1, we will use cell-specific knock-down and rescue to determine if ETR-1 acts in muscles for Q migrations. In aim 2, we will use fluorescent-activated cell sorting of body wall muscles combined with RNA-seq in wild-type and etr-1 mutants to define transcripts affected by etr-1 that might regulate Q migrations. Because of our novel and innovative approach, new genes and gene interactions that regulate neuroblast migration will be discovered.