Nucleo-cytoplasmic shuttling of splicing factor SRSF1 is required for development and cilia function

• Published in: eLife Vol. 10
• Main Authors: Haward, Fiona, Maslon, Magdalena M, Yeyati, Patricia L, Bellora, Nicolas, Hansen, Jan N, Aitken, Stuart, Lawson, Jennifer, von Kriegsheim, Alex, Wachten, Dagmar, Mill, Pleasantine, Adams, Ian R, Caceres, Javier F
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 02.08.2021; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: alternative splicing; Analysis; Animals; Binding proteins; Biochemistry and Chemical Biology; Body size; Cell cycle; Cell Nucleus - metabolism; Chromosomes and Gene Expression; Cilia; Cilia - metabolism; CRISPR; Cytoplasm; Cytoplasm - metabolism; Gene expression; Genome editing; Genomes; Genomics; Hydrocephalus; Kinases; Localization; Male; Mice; motile cilia; mRNA translation; Physiological aspects; Protein binding; Proteins; RNA; RNA polymerase; RNA-binding protein; RNA-binding proteins; Serine-Arginine Splicing Factors - genetics; Serine-Arginine Splicing Factors - metabolism; Splicing factors; SR proteins; SRSF1; Stem cells; Testes; Ultrastructure; Canada; SR proteins; mouse; mRNA translation; alternative splicing; chemical biology; SRSF1; biochemistry; chromosomes; motile cilia; RNA-binding proteins; gene expression
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/ELIFE.65104

Shuttling RNA-binding proteins coordinate nuclear and cytoplasmic steps of gene expression. The SR family proteins regulate RNA splicing in the nucleus and a subset of them, including SRSF1, shuttles between the nucleus and cytoplasm affecting post-splicing processes. However, the physiological significance of this remains unclear. Here, we used genome editing to knock-in a nuclear retention signal (NRS) in to create a mouse model harboring an SRSF1 protein that is retained exclusively in the nucleus. mutants displayed small body size, hydrocephalus, and immotile sperm, all traits associated with ciliary defects. We observed reduced translation of a subset of mRNAs and decreased abundance of proteins involved in multiciliogenesis, with disruption of ciliary ultrastructure and motility in cells and tissues derived from this mouse model. These results demonstrate that SRSF1 shuttling is used to reprogram gene expression networks in the context of high cellular demands, as observed here, during motile ciliogenesis.