<scp>RBM</scp>20 and <scp>RBM</scp>24 cooperatively promote the expression of short <i>enh</i> splice variants

Ito, Jin‐ichi; Iijima, Masumi; Yoshimoto, Nobuo; Niimi, Tomoaki; Kuroda, Shinya; Maturana, Andrés D.

doi:10.1002/1873-3468.12251

Cited by 27 publications

(26 citation statements)

References 38 publications

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“…The highly conserved Rbm24 protein contains a single RNA recognition motif (RRM) and exhibits tissue-specific expression patterns in all vertebrate species. It plays an important role in skeletal and cardiac muscle development (21)(22)(23)(24) by regulating mRNA stability (25,26), pre-mRNA splicing (24,(27)(28)(29)(30), and mRNA translation (31). Moreover, its expression in head sensory organs, particularly in the lens, is also conserved in vertebrates (23,32).…”

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confidence: 99%

Rbm24 controls poly(A) tail length and translation efficiency of crystallin mRNAs in the lens via cytoplasmic polyadenylation

Shao

Lü

Zhang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Lens transparency is established by abundant accumulation of crystallin proteins and loss of organelles in the fiber cells. It requires an efficient translation of lens messenger RNAs (mRNAs) to overcome the progressively reduced transcriptional activity that results from denucleation. Inappropriate regulation of this process impairs lens differentiation and causes cataract formation. However, the regulatory mechanism promoting protein synthesis from lens-expressed mRNAs remains unclear. Here we show that in zebrafish, the RNAbinding protein Rbm24 is critically required for the accumulation of crystallin proteins and terminal differentiation of lens fiber cells. In the developing lens, Rbm24 binds to a wide spectrum of lens-specific mRNAs through the RNA recognition motif and interacts with cytoplasmic polyadenylation element-binding protein (Cpeb1b) and cytoplasmic poly(A)-binding protein (Pabpc1l) through the C-terminal region. Loss of Rbm24 reduces the stability of a subset of lens mRNAs encoding heat shock proteins and shortens the poly(A) tail length of crystallin mRNAs encoding lens structural components, thereby preventing their translation into functional proteins. This severely impairs lens transparency and results in blindness. Consistent with its highly conserved expression in differentiating lens fiber cells, the findings suggest that vertebrate Rbm24 represents a key regulator of cytoplasmic polyadenylation and plays an essential role in the posttranscriptional control of lens development.Rbm24 | lens | cataract | cytoplasmic polyadenylation | zebrafish

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confidence: 99%

Rbm24 controls poly(A) tail length and translation efficiency of crystallin mRNAs in the lens via cytoplasmic polyadenylation

Shao

Lü

Zhang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Another protein partner of RBM20 is RBM24, and these two factors co-regulate inclusion of exon 11 from Enh pre-mRNA (Ito et al, 2016). A direct interaction was found in vitro between the full-length RBM20 and RBM24 proteins, and a cooperative binding by both proteins might help define target specificity to the region upstream of exon 11.…”

Section: In Terms Of Protein-protein Interactions Polypyrimidine Tramentioning

confidence: 99%

“…A direct interaction was found in vitro between the full-length RBM20 and RBM24 proteins, and a cooperative binding by both proteins might help define target specificity to the region upstream of exon 11. In support of functional cooperativity, single mouse knockouts of RBM20 or RBM24 have only minimal effect on exon 11, whereas simultaneously increasing or decreasing RBM20 and RBM24 shifts Enh towards the long or short isoform, respectively (Ito et al, 2016).…”

Section: In Terms Of Protein-protein Interactions Polypyrimidine Tramentioning

confidence: 99%

“…Human, rat and mouse studies identified additional splicing targets that encode proteins which bind and transport Ca 2+ (Guo et al, 2012;van den Hoogenhof et al, 2018;Guo et al, 2018;Maatz et al, 2014;Wyles et al, 2016;Beraldi et al, 2014) such as the calcium channel ryanodine receptor 2 (RYR2), Ca 2+ /calmodulin-dependent protein kinase II delta (CAMK2δ), and the calcium channel voltage-gated L type alpha 1C subunit (CACNA1C/Cav1.2). Other characterized targets include formin homology 2 domain containing 3 (FHOD3), Z-band alternatively spliced PDZ-motif protein (ZASP/LDB3/CYPHER), and the PDZ and LIM domain protein 5 (PDLIM5/ENH) (Maatz et al, 2014;Guo et al, 2012;Lorenzi et al, 2019;Ito et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Structural basis of UCUU RNA motif recognition by splicing factor RBM20

Upadhyay

Mackereth

2019

Preprint

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The vertebrate splicing factor RBM20 (RNA Binding Motif protein 20) regulates protein isoforms important for heart development and function, with mutations in the gene linked to cardiomyopathy. Previous studies have identified the four base RNA motif UCUU as a common element in pre-mRNA targeted by RBM20. Here, we have determined the structure of the RNA Recognition Motif (RRM) domain from mouse RBM20 bound to RNA containing a UCUU sequence. The atomic details show that the RRM domain spans a larger region than initially proposed in order to interact with the complete UCUU motif, with a well-folded Cterminal helix encoded by exon 8 critical for high affinity binding. This helix only forms upon binding RNA with the final uracil, and removing the helix reduces affinity as well as specificity. We therefore find that RBM20 uses a coupled folding-binding mechanism by the C-terminal helix to specifically recognize the UCUU RNA motif.

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“…20 Defects in RBM20 are associated with an increased ratio of ENH1/ENH3, which promotes hypertrophy of cardiac myofibers and is hypothesized to be a mechanism of cardiomyopathy in humans. 20 The Rbm20-defective rat was discovered by chance during a developmental study on the giant protein TTN. 13 Differently sized TTN isoforms are expressed from a single gene via alternative splicing in an age-dependent manner.…”

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Megaesophagus Is a Major Pathological Condition in Rats With a Large Deletion in the Rbm20 Gene

2019

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A spontaneously arising, loss-of-function mutation in the RNA binding motif protein 20 (Rbm20) gene, which encodes a nuclear splicing protein, was previously identified as the underlying reason for expression of an abnormally large TITIN (TTN) protein in a rat model of cardiomyopathy. An outbreak of Pseudomonas aeruginosa led to submission of rats with dyspnea, sneezing, lethargy, nasal discharge, and/or unexpected death for diagnostic evaluation. Necropsy revealed underlying megaesophagus in Rbm20 -/rats. Further phenotyping of this rat strain and determination of the size of esophageal TTN was undertaken. The Rbm20defective rats developed megaesophagus at an early age (26 weeks) with high frequency (13/32, 41%). They also often exhibited secondary rhinitis (9/32, 28%), aspiration pneumonia (8/32, 25%), and otitis media/interna (6/32, 19%). In addition, these rats had a high prevalence of hydronephrosis (13/32, 41%). RBM20 is involved in splicing multiple RNA transcripts, one of which is the muscle-specific protein TTN. Rbm20 mutations are a significant cause of dilated cardiomyopathy in humans. In Rbm20-defective rats, TTN size was significantly increased in the skeletal muscle of the esophagus. Megaesophagus in this rat strain (maintained on a mixed genetic background) is hypothesized to result from altered TTN stretch signaling in esophageal skeletal muscle. This study describes a novel mechanism for the development of megaesophagus, which may be useful for understanding the pathogenesis of megaesophagus in humans and offers insights into potential myogenic causes of this condition. This is the first report of megaesophagus and other noncardiac pathogenic changes associated with mutation of Rbm20 in any species.

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RBM20 and RBM24 cooperatively promote the expression of short enh splice variants

Cited by 27 publications

References 38 publications

Rbm24 controls poly(A) tail length and translation efficiency of crystallin mRNAs in the lens via cytoplasmic polyadenylation

Rbm24 controls poly(A) tail length and translation efficiency of crystallin mRNAs in the lens via cytoplasmic polyadenylation

Structural basis of UCUU RNA motif recognition by splicing factor RBM20

Megaesophagus Is a Major Pathological Condition in Rats With a Large Deletion in the Rbm20 Gene

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