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Title: Early developmental arrest and impaired gastrointestinal homeostasis in U12-dependent splicing-defective Rnpc3-deficient mice.
Austin Authors: Doggett, Karen;Williams, Ben B;Markmiller, Sebastian;Geng, Fan-Suo;Coates, Janine;Mieruszynski, Stephen;Ernst, Matthias ;Thomas, Tim;Heath, Joan K
Affiliation: Walter and Eliza Hall Institute of Medical Research
University of Melbourne
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Issue Date: Dec-2018
Date: 2018-09-25
Publication information: RNA (New York, N.Y.) 2018; 24(12): 1856-1870
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.
DOI: 10.1261/rna.068221.118
ORCID: 0000-0002-6399-1177
Journal: RNA (New York, N.Y.)
PubMed URL: 30254136
Type: Journal Article
Subjects: Development
Gastrointestinal epithelium
Minor class splicing
U12-type intron
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