New insights into the centrosome‐associated spliceosome components as regulators of ciliogenesis and tissue identity

Abstract

Biomolecular condensates are membrane-less assemblies of proteins and nucleic acids. Centrosomes are biomolecular condensates that play a crucial role in nuclear division, cytoskeletal remodeling, and cilia formation in animal cells. Spatial omics technology is providing new insights into the dynamic exchange of spliceosome components between the nucleus and the centrosome/cilium. Intriguingly, centrosomes are emerging as cytoplasmic sites for information storage, enriched with RNA molecules and RNA-processing proteins. Furthermore, growing evidence supports the view that nuclear spliceosome components assembled at the centrosome function as potential coordinators of splicing subprograms, pluripotency, and cell differentiation.In this article, we first discuss the current understanding of the centrosome/cilium complex, which controls both stem cell differentiation and pluripotency. We next explore the molecular mechanisms that govern splicing factor assembly and disassembly around the centrosome and examine how RNA processing pathways contribute to ciliogenesis. Finally, we discuss numerous unresolved compelling questions regarding the centrosomeassociated spliceosome components and transcript variants within the cytoplasm as sources of RNA-based secondary messages in the regulation of cell identity and cell fate determination.

GPATCH11variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment

“…This examination not only confirmed the expected nuclear localization of the GPATCH11 protein 9 but also revealed a distinctive foci staining pattern (through methanol fixation) and a diffuse presence in the nucleoplasm, in addition to a centrosomal localization. This distribution pattern aligns with what has been previously described for centrosome-associated spliceosome components 10,11 . Of note, basal body staining was decreased in PFA-fixed cells ( Supplementary Fig.…”

“…Very interestingly, alongside with a nuclear distribution, we observed GPATCH11 in the centrosome. The nuclear and centrosomal/cilia distribution of GPATCH11 aligns with recent findings describing it as a characteristic feature of spliceosome proteins known as centrosome-associated spliceosome components emerging as crucial players in ciliogenesis and tissue specification, reshaping our understanding of RNA metabolism within the cell 11 . Until recent years, the conventional belief that pre-mRNA splicing exclusively takes place within the nucleus faced challenges, primarily due to reports of centrosome/cilia enrichment of both non-coding and coding RNA, along with dedicated translation machinery.…”

“…Centrosome-associated spliceosome components have previously been reported as regulators of ciliogenesis 11 . Therefore, we aimed to investigate whether the GPATCH- or CCDC-domains of GPATCH11 play a role in cilia formation.…”

“…Furthermore, the localization of spliceosomal components to these cellular regions further questioned this traditional view. This centrosome-associated RNA machinery is hypothesized to facilitate the nucleocytoplasmic shuttling of RNA between the spliceosome and the cytoplasm 11 .…”

The cilium–centrosome axis in coupling cell cycle exit and cell fate

“…Components of mRNA biogenesis and trafficking [including the spliceosome, pre-mRNA-processing factors (PRPFs), the exon junction complex (EJC) and the transcription-and-export complex (TREX)] not only enable mRNA surveillance mechanisms (Le Hir et al, 2016) but also localize to the C/BB (Busselez et al, 2023) to regulate cilium-centrosome function and coordinate fate choice (Haward et al, 2021;Michlewski et al, 2008;O'Neill et al, 2022;Stemm-Wolf et al, 2021). PRPFs also localize to the C/BB (Wheway et al, 2015) and differentially regulate C/BB composition in neural stem cells (NSCs) and neurons via localization of target mRNAs (O'Neill et al, 2022).…”