The Emerging Significance of Splicing in Vertebrate Development

Overview

Journal Development

Specialty Biology

Date 2022 Sep 30

PMID 36178052

Authors

Anouk M Olthof

Alisa K White

Rahul N Kanadia

Affiliations

Soon will be listed here.

Abstract

Splicing is a crucial regulatory node of gene expression that has been leveraged to expand the proteome from a limited number of genes. Indeed, the vast increase in intron number that accompanied vertebrate emergence might have aided the evolution of developmental and organismal complexity. Here, we review how animal models for core spliceosome components have provided insights into the role of splicing in vertebrate development, with a specific focus on neuronal, neural crest and skeletal development. To this end, we also discuss relevant spliceosomopathies, which are developmental disorders linked to mutations in spliceosome subunits. Finally, we discuss potential mechanisms that could underlie the tissue-specific phenotypes often observed upon spliceosome inhibition and identify gaps in our knowledge that, we hope, will inspire further research.

Citing Articles

Connecting genotype and phenotype in minor spliceosome diseases.

Norppa A, Shcherbii M, Frilander M RNA. 2025; 31(3):284-299.

PMID: 39761998 PMC: 11874965. DOI: 10.1261/rna.080337.124.

Pharmacological Inhibition of the Spliceosome SF3b Complex by Pladienolide-B Elicits Craniofacial Developmental Defects in Mouse and Zebrafish.

Hoshino Y, Liu S, Furutera T, Yamada T, Koyabu D, Nukada Y Birth Defects Res. 2024; 116(11):e2404.

PMID: 39494782 PMC: 11579809. DOI: 10.1002/bdr2.2404.

Circular RNAs regulate neuron size and migration of midbrain dopamine neurons during development.

Rybiczka-Tesulov M, Garritsen O, Veno M, Wieg L, Dijk R, Rahimi K Nat Commun. 2024; 15(1):6773.

PMID: 39117691 PMC: 11310423. DOI: 10.1038/s41467-024-51041-1.

Taxonomy of introns and the evolution of minor introns.

Olthof A, Schwoerer C, Girardini K, Weber A, Doggett K, Mieruszynski S Nucleic Acids Res. 2024; 52(15):9247-9266.

PMID: 38943346 PMC: 11347168. DOI: 10.1093/nar/gkae550.

Regulation of alternative splicing and polyadenylation in neurons.

Lee S, Aubee J, Lai E Life Sci Alliance. 2023; 6(12).

PMID: 37793776 PMC: 10551640. DOI: 10.26508/lsa.202302000.

References

Martin E, Vivori C, Rogalska M, Herrero-Vicente J, Valcarcel J . Alternative splicing regulation of cell-cycle genes by SPF45/SR140/CHERP complex controls cell proliferation. RNA. 2021; 27(12):1557-1576. PMC: 8594467. DOI: 10.1261/rna.078935.121. View

Olthof A, White A, Mieruszynski S, Doggett K, Lee M, Chakroun A . Disruption of exon-bridging interactions between the minor and major spliceosomes results in alternative splicing around minor introns. Nucleic Acids Res. 2021; 49(6):3524-3545. PMC: 8034651. DOI: 10.1093/nar/gkab118. View

Gabut M, Samavarchi-Tehrani P, Wang X, Slobodeniuc V, OHanlon D, Sung H . An alternative splicing switch regulates embryonic stem cell pluripotency and reprogramming. Cell. 2011; 147(1):132-46. DOI: 10.1016/j.cell.2011.08.023. View

Madan V, Cao Z, Teoh W, Dakle P, Han L, Shyamsunder P . ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells. Haematologica. 2021; 107(3):680-689. PMC: 8883539. DOI: 10.3324/haematol.2020.260562. View

Kleinridders A, Pogoda H, Irlenbusch S, Smyth N, Koncz C, Hammerschmidt M . PLRG1 is an essential regulator of cell proliferation and apoptosis during vertebrate development and tissue homeostasis. Mol Cell Biol. 2009; 29(11):3173-85. PMC: 2682009. DOI: 10.1128/MCB.01807-08. View

White A, Baumgartner M, Lee M, Drake K, Aquino G, Kanadia R . Trp53 ablation fails to prevent microcephaly in mouse pallium with impaired minor intron splicing. Development. 2021; 148(20). PMC: 8572008. DOI: 10.1242/dev.199591. View

Sorrells S, Nik S, Casey M, Cameron R, Truong H, Toruno C . Spliceosomal components protect embryonic neurons from R-loop-mediated DNA damage and apoptosis. Dis Model Mech. 2018; 11(2). PMC: 5894942. DOI: 10.1242/dmm.031583. View

Henson H, Taylor M . A Zebrafish Mutant Results in Developmental Defects in the Central Nervous System. Cells. 2020; 9(11). PMC: 7690441. DOI: 10.3390/cells9112340. View

Forman T, Dennison B, Fantauzzo K . The Role of RNA-Binding Proteins in Vertebrate Neural Crest and Craniofacial Development. J Dev Biol. 2021; 9(3). PMC: 8482138. DOI: 10.3390/jdb9030034. View

10.

Strikoudis A, Lazaris C, Trimarchi T, Galvao Neto A, Yang Y, Ntziachristos P . Regulation of transcriptional elongation in pluripotency and cell differentiation by the PHD-finger protein Phf5a. Nat Cell Biol. 2016; 18(11):1127-1138. PMC: 5083132. DOI: 10.1038/ncb3424. View

11.

Baralle F, Giudice J . Alternative splicing as a regulator of development and tissue identity. Nat Rev Mol Cell Biol. 2017; 18(7):437-451. PMC: 6839889. DOI: 10.1038/nrm.2017.27. View

12.

Santos A, Wernersson R, Jensen L . Cyclebase 3.0: a multi-organism database on cell-cycle regulation and phenotypes. Nucleic Acids Res. 2014; 43(Database issue):D1140-4. PMC: 4383920. DOI: 10.1093/nar/gku1092. View

13.

Xu Y, Zhao W, Olson S, Prabhakara K, Zhou X . Alternative splicing links histone modifications to stem cell fate decision. Genome Biol. 2018; 19(1):133. PMC: 6138936. DOI: 10.1186/s13059-018-1512-3. View

14.

He H, Liyanarachchi S, Akagi K, Nagy R, Li J, Dietrich R . Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I. Science. 2011; 332(6026):238-40. PMC: 3380448. DOI: 10.1126/science.1200587. View

15.

Olthof A, Rasmussen J, Campeau P, Kanadia R . Disrupted minor intron splicing is prevalent in Mendelian disorders. Mol Genet Genomic Med. 2020; 8(9):e1374. PMC: 7507305. DOI: 10.1002/mgg3.1374. View

16.

Tanackovic G, Kramer A . Human splicing factor SF3a, but not SF1, is essential for pre-mRNA splicing in vivo. Mol Biol Cell. 2005; 16(3):1366-77. PMC: 551499. DOI: 10.1091/mbc.e04-11-1034. View

17.

Beauchamp M, Djedid A, Daupin K, Clokie K, Kumar S, Majewski J . Loss of function mutation of Eftud2, the gene responsible for mandibulofacial dysostosis with microcephaly (MFDM), leads to pre-implantation arrest in mouse. PLoS One. 2019; 14(7):e0219280. PMC: 6611600. DOI: 10.1371/journal.pone.0219280. View

18.

Devotta A, Juraver-Geslin H, Gonzalez J, Hong C, Saint-Jeannet J . Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome. Dev Biol. 2016; 415(2):371-382. PMC: 4914463. DOI: 10.1016/j.ydbio.2016.02.010. View

19.

Chai G, Webb A, Li C, Antaki D, Lee S, Breuss M . Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly. Neuron. 2020; 109(2):241-256.e9. PMC: 8800389. DOI: 10.1016/j.neuron.2020.10.035. View

20.

Jokoji G, Maeda S, Oishi K, Ijuin T, Nakajima M, Tawaratsumida H . CDC5L promotes early chondrocyte differentiation and proliferation by modulating pre-mRNA splicing of SOX9, COL2A1, and WEE1. J Biol Chem. 2021; 297(2):100994. PMC: 8363834. DOI: 10.1016/j.jbc.2021.100994. View