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

eLife

Alex von Kriegsheim¹  Dagmar Wachten²  Jan N Hansen²  Nicolas Bellora³  Stuart Aitken⁴  Pleasantine Mill⁴  Ian R Adams⁴  Javier F Caceres⁴  Patricia L Yeyati⁴  Fiona Haward⁴  Magdalena M Maslon⁴  Jennifer Lawson⁴ 

[1] Edinburgh Cancer Research United Kingdom Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom;Institute of Innate Immunity, Biophysical Imaging, Medical Faculty, University of Bonn, Bonn, Germany;Institute of Nuclear Technologies for Health (Intecnus), National Scientific and Technical Research Council (CONICET), Bariloche, Argentina;MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom;

关键词: SR proteins;    SRSF1;    RNA-binding proteins;    alternative splicing;    mRNA translation;    motile cilia;    Mouse;   

DOI  :  10.7554/eLife.65104

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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 Srsf1 to create a mouse model harboring an SRSF1 protein that is retained exclusively in the nucleus. Srsf1NRS/NRS 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.

【 授权许可】

CC BY