The RNA-binding protein Rbm38 is dispensable during pressure overload-induced cardiac remodeling in mice

Abstract

The importance of tightly controlled alternative pre-mRNA splicing in the heart is emerging. The RNA binding protein Rbm24 has recently been identified as a pivotal cardiac splice factor, which governs sarcomerogenesis in the heart by controlling the expression of alternative protein isoforms. Rbm38, a homolog of Rbm24, has also been implicated in RNA processes such as RNA splicing, RNA stability and RNA translation, but its function in the heart is currently unknown. Here, we investigated the role of Rbm38 in the healthy and diseased adult mouse heart. In contrast to the heart- and skeletal muscle-enriched protein Rbm24, Rbm38 appears to be more broadly expressed. We generated somatic Rbm38 -/- mice and show that global loss of Rbm38 results in hematopoietic defects. Specifically, Rbm38 -/- mice were anemic and displayed enlarged spleens with extramedullary hematopoiesis, as has been shown earlier. The hearts of Rbm38 -/- mice were mildly hypertrophic, but cardiac function was not affected. Furthermore, Rbm38 deficiency did not affect cardiac remodeling (i.e. hypertrophy, LV dilation and fibrosis) or performance (i.e. fractional shortening) after pressure-overload induced by transverse aorta constriction. To further investigate molecular consequences of Rbm38 deficiency, we examined previously identified RNA stability, splicing, and translational targets of Rbm38. We found that stability targets p21 and HuR, splicing targets Mef2d and Fgfr2, and translation target p53 were not altered, suggesting that these Rbm38 targets are tissue-specific or that Rbm38 deficiency may be counteracted by a redundancy mechanism. In this regard, we found a trend towards increased Rbm24 protein expression in Rbm38 -/- hearts. Overall, we conclude that Rbm38 is critical in hematopoiesis, but does not play a critical role in the healthy and diseased heart.

AAV9-mediated Rbm24 overexpression induces fibrosis in the mouse heart

“…Per section, 5 pictures were taken from the LV using a light microscope (20x magnification). Fibrosis quantification was done using an in-house macro in ImagePro 6.2 12 . Perivascular fibrosis was manually omitted from the pictures.…”

“…The role of Rbm24 in the postnatal and adult heart, however, is yet unknown. We have recently shown that Rbm38, a closely related family member of Rbm24, is dispensable for normal cardiac function, both at baseline and after pressure overload-induced cardiac remodeling 12 . Rbm24 and Rbm38 share 68% of sequence identity, which suggests they could be genetically redundant 12 .…”

“…We have recently shown that Rbm38, a closely related family member of Rbm24, is dispensable for normal cardiac function, both at baseline and after pressure overload-induced cardiac remodeling 12 . Rbm24 and Rbm38 share 68% of sequence identity, which suggests they could be genetically redundant 12 . We hypothesized that, since Rbm38 is dispensable for proper cardiac structure and function, Rbm24 might be more important in the adult heart.…”

mRNA Metabolism in Cardiac Development and Disease: Life After Transcription

“…With the use of an inducible RBM24 expression system, it was demonstrated that RBM24 can also regulate a large number of alternative splicing events during mouse embryonic stem cell differentiation ( 242 ). RBM38, a homolog of RBM24, can also function in mRNA splicing and stability, but is dispensable for pressure overload-induced cardiac remodeling ( 205 ). Finally, RBM10 mutations may be causal of the talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava (TARP) syndrome ( 77a ).…”

Therapeutic modulation of RNA-binding protein Rbm38 facilitates re-endothelialization after arterial injury

“…the drug and radiation resistance 12 . Somatic Rbm38 knockout (−/−) mice expressed haematopoietic defects 13 , 14 and loss of Rbm38 lead to T-cell lymphomagenesis 15 . Also the role of Rbm38 on cardiac remodelling was recently examined, 14 but the function of Rbm38 in endothelial cells is still unclear.…”