Exon junction complex dependent mRNA localization is linked to centrosome organization during ciliogenesis

Abstract

Exon junction complexes (EJCs) mark untranslated spliced mRNAs and are crucial for the mRNA lifecycle. An imbalance in EJC dosage alters mouse neural stem cell (mNSC) division and is linked to human neurodevelopmental disorders. In quiescent mNSC and immortalized human retinal pigment epithelial (RPE1) cells, centrioles form a basal body for ciliogenesis. Here, we report that EJCs accumulate at basal bodies of mNSC or RPE1 cells and decline when these cells differentiate or resume growth. A high-throughput smFISH screen identifies two transcripts accumulating at centrosomes in quiescent cells, NIN and BICD2. In contrast to BICD2, the localization of NIN transcripts is EJC-dependent. NIN mRNA encodes a core component of centrosomes required for microtubule nucleation and anchoring. We find that EJC down-regulation impairs both pericentriolar material organization and ciliogenesis. An EJC-dependent mRNA trafficking towards centrosome and basal bodies might contribute to proper mNSC division and brain development.

The Identification and Functional Analysis of mRNA Localizing to Centrosomes

“…In support of this hypothesis, ribosomes co-purify with microtubules (Goldman and Rebhun, 1969), and ribosomal proteins decorate centrosomes and spindle poles (Blower et al, 2007;Sepulveda et al, 2018;Chouaib et al, 2020;Pascual et al, 2020;Kwon et al, 2021). Persuasive evidence for polyribosomes located near centrosomes comes from ultrastructural analysis; for example, see figure 18 in (Sorokin, 1962) and Plate 10 in (Murray et al, 1965).…”

“…RNA localization to the centrosome is, however, remarkably specific. As evidenced by genome-wide screens, relatively few transcripts reside at the centrosome ( Lecuyer et al, 2007 ; Wilk et al, 2016 ; Chouaib et al, 2020 ; Kwon et al, 2021 ; Safieddine et al, 2021 ). The unique distributions of specific mRNAs rely upon cis -sequences, nascent peptides, and/or structural motifs within the RNA being recognized by trans -acting RNA-binding proteins.…”

p53 Activation in Genetic Disorders: Different Routes to the Same Destination

“…Notably, transcriptome analysis reveals a reduction in the expression of ribosomal protein mRNAs, indicating that Rbm8a deficiency may compromise ribosome biogenesis [64]. Rbm8a deficiency also results in centrosome aberrations and DNA damage accumulation [66][67][68], which have the potential to induce p53. In addition, RBM8A (Y14) depletion inhibits ubiquitination of p53 and thus stabilizes p53 in cell cultures [69].…”

“…Recent reports have indicated that Fanca and Fanci play a role in ribosome biogenesis or nucleolar homeostasis, suggesting a potential link between DNA damage and nucleolar stress responses [123]. In addition to mRNA surveillance, RBM8A participates in DNA damage repair and centrosome organization [66][67][68]. It is conceivable that several critical cellular processes that span genome integrity, mRNA/protein expression, and cell cycle/division, are interrelated to ensure proper cellular function.…”

Drosophila centrocortin is dispensable for centriole duplication but contributes to centrosome separation

“…Centrosome function as a MTOC is instructed by the pericentriolar material (PCM), a matrix of proteins that encircles the central pair of centrioles (Nigg and Raff 2009). RNAs also localize to centrosomes, and local mRNAs may contribute to centrosome functions, likely through a co-translational transport mechanism (Marshall and Rosenbaum 2000;Sepulveda et al 2018;Chouaib et al 2020;Kwon et al 2021;Safieddine et al 2021). For example, recent work indicates centrocortin (cen) mRNA localized to centrosomes is required for error-free mitosis in rapidly dividing, syncytial Drosophila embryos (Bergalet et al 2020;Ryder et al2020).…”