Early developmental arrest and impaired gastrointestinal homeostasis in U12-dependent splicing-defective Rnpc3-deficient mice
Details
Publication Year 2018-12, Volume 24, Issue #12, Page 1856-1870
Journal Title
RNA
Publication Type
Journal Article
Abstract
Splicing is an essential step in eukaryotic gene expression. While the majority of introns is excised by the U2-dependent, or major class, spliceosome, the appropriate expression of a very small subset of genes depends on U12-dependent, or minor class, splicing. The U11/U12 65K protein (hereafter 65K), encoded by RNPC3, is one of seven proteins that are unique to the U12-dependent spliceosome, and previous studies, including our own, have established that it plays a role in plant and vertebrate development. To pin-point the impact of 65K loss during mammalian development and in adulthood, we generated germline and conditional Rnpc3-deficient mice. Homozygous Rnpc3-/- embryos died prior to blastocyst implantation, whereas Rnpc3+/- mice were born at the expected frequency, achieved sexual maturity and exhibited a completely normal lifespan. Systemic recombination of conditional Rnpc3 alleles in adult (Rnpc3lox/lox) mice caused rapid weight loss, leukopenia and degeneration of the epithelial lining of the entire gastrointestinal tract, the latter due to increased cell death and a reduction in cell proliferation. Accompanying this, we observed a loss of both 65K and the pro-proliferative phospho-ERK1/2 proteins from the stem/progenitor cells at the base of intestinal crypts. RT-PCR analysis of RNA extracted from purified preparations of intestinal epithelial cells with recombined Rnpc3lox alleles revealed increased frequency of U12-type intron retention in all transcripts tested. Our study, using a novel conditional mouse model of Rnpc3 deficiency, establishes that U12-dependent splicing is not only important during development but is indispensable throughout life.
Publisher
CSH Press
WEHI Research Division(s)
Development And Cancer
PubMed ID
30254136
Open Access at Publisher's Site
https://doi.org/10.1261/rna.068221.118
NHMRC Grants
NHMRC/1024878 NHMRC/1022870
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2018-10-11 04:23:14
Last Modified: 2018-12-05 02:57:29
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