Abstract
SR family RNA binding proteins regulate splicing of nascent RNAs in vitro but their physiological role in vivo is largely unexplored, as genetic deletion of many SR protein genes results in embryonic lethality. Here we show that SRSF3HKO mice carrying a hepatocyte-specific deletion of Srsf3 (homologous to human SRSF3/SRp20) have a disrupted hepatic architecture and show pre- and postnatal growth retardation. SRSF3HKO mice exhibit impaired hepatocyte maturation with alterations in glucose and lipid homeostasis characterized by reduced glycogen storage, fasting hypoglycemia, increased insulin sensitivity and reduced cholesterol synthesis. We identify various splicing alterations in the SRSF3HKO liver that explain the in vivo phenotype. In particular, loss of SRSF3 causes aberrant splicing of Hnf1α, Ern1, Hmgcs1, Dhcr7 and Scap genes, which are critical regulators of glucose and lipid metabolism. Our study provides the first evidence for a SRSF3-driven genetic programme required for morphological and functional differentiation of hepatocytes that may have relevance for human liver disease and metabolic dysregulation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Alternative Splicing / drug effects
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Alternative Splicing / genetics
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Animals
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Base Sequence
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Biomarkers / metabolism
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Cell Differentiation* / drug effects
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Cell Differentiation* / genetics
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Cholesterol / metabolism
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Exons / genetics
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Glucose / metabolism
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Growth Hormone / pharmacology
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Hepatocytes / cytology*
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Hepatocytes / drug effects
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Hepatocytes / metabolism*
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Homeostasis / drug effects
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Homeostasis / genetics
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Humans
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Liver / drug effects
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Liver / metabolism
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Liver / pathology
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Mice
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Mice, Knockout
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Models, Biological
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Molecular Sequence Data
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Oligonucleotide Array Sequence Analysis
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA-Binding Proteins / metabolism*
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Serine-Arginine Splicing Factors
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Triglycerides / metabolism
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Unfolded Protein Response / drug effects
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Unfolded Protein Response / genetics
Substances
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Biomarkers
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RNA, Messenger
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RNA-Binding Proteins
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Srsf3 protein, mouse
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Triglycerides
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Serine-Arginine Splicing Factors
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Growth Hormone
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Cholesterol
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Glucose