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And Post-Transcriptional Regulation of Rbm5 and Rbm10 in Mouse Cells As Evidenced by Tissue-Specific, Developmental and Dise

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And Post-Transcriptional Regulation of Rbm5 and Rbm10 in Mouse Cells As Evidenced by Tissue-Specific, Developmental and Dise Gene 580 (2016) 26–36 Contents lists available at ScienceDirect Gene journal homepage: www.elsevier.com/locate/gene Research paper Co- and post-transcriptional regulation of Rbm5 and Rbm10 in mouse cells as evidenced by tissue-specific, developmental and disease-associated variation of splice variant and protein expression levels Bartholomew Ozuemba a, Twinkle J. Masilamani b, Julie J. Loiselle b, Benjamin Koenderink c, Kaitlin A. Vanderbeck d, Jose Knee c, Céline Larivière b,d,LeslieC.Sutherlandb,c,e,f,g,⁎ a School of Life Science, University of Skovde, 541 28 Skovde, Sweden b Biomolecular Sciences Program, Laurentian University, 935 Ramsey Lake Road, Sudbury, ON, P3E 2C6, Canada c AMRIC, Health Sciences North, 41 Ramsey Lake Road, Sudbury, ON, P3E 5J1, Canada d School of Human Kinetics, Laurentian University, 935 Ramsey Lake Road, Sudbury, ON, P3E 2C6, Canada e Division of Medical Sciences, Northern Ontario School of Medicine, Laurentian University, 935 Ramsey Lake Road, Sudbury, ON, P3E 2C6, Canada f Department of Chemistry and Biochemistry, Laurentian University, 935 Ramsey Lake Road, Sudbury, ON, P3E 2C6, Canada g Department of Medicine, Division of Medical Oncology, University of Ottawa, Ottawa, ON, Canada article info abstract Article history: Background: Expression and function of the two RNA binding proteins and regulators of alternative splicing, Received 5 November 2015 RBM5 and RBM10, have largely been studied in human tissue and cell lines. The objective of the study described Accepted 31 December 2015 herein was to examine their expression in mouse tissue, in order to lay the framework for comprehensive func- Available online 16 January 2016 tional studies using mouse models. Methods: All RNA variants of Rbm5 and Rbm10 were examined in a range of normal primary mouse tissues. RNA Keywords: and protein were examined in differentiating C2C12 myoblasts and in denervated and dystonin-deficient mouse RBM5 skeletal muscle. RBM10 Gene expression Results: All Rbm5 and Rbm10 variants examined were expressed in all mouse tissues and cell lines. In general, Mouse Rbm5 and Rbm10 RNA expression was higher in brain than in skin. RNA expression levels were more varied be- Primary tissue tween cardiac and skeletal muscle, depending on the splice variant: for instance, Rbm10v1 RNA was higher in C2C12 skeletal than cardiac muscle, whereas Rbm10v3 RNA was higher in cardiac than skeletal muscle. In mouse Denervation brain, cardiac and skeletal muscle, RNA encoding an approximately 17 kDa potential paralogue of a small human RBM10 isoform was detected, and the protein observed in myoblasts and myotubes. Expression of Rbm5 and Rbm10 RNA remained constant during C2C12 myogenesis, but protein levels significantly decreased. In two muscle disease models, neither Rbm10 nor Rbm5 showed significant transcriptional changes, although sig- nificant specific alternative splicing changes of Rbm5 pre-mRNA were observed. Increased RBM10 protein levels were observed following denervation. Conclusions: The varied co-transcriptional and post-transcriptional regulation aspects of Rbm5 and Rbm10 ex- pression associated with mouse tissues, myogenesis and muscle disease states suggest that a mouse model would be an interesting and useful model in which to study comprehensive functional aspects of RBM5 and RBM10. © 2016 Elsevier B.V. All rights reserved. 1. Introduction Changes in RBP expression, with consequences for various RNA- related processes, are linked to many disease states including cancer, RNA Binding Proteins (RBPs) are key players in all aspects of RNA neurological disorders and muscular dystrophies (Lukong et al., 2008; metabolism including splicing, processing, stability and transport. Kim et al., 2009; Musunuru, 2003). RNA Binding Motif (RBM) proteins RBM5 and RBM10 are two structurally related proteins involved in the regulation of alternative splicing and, in the case of RBM10, mRNA sta- Abbreviations: D, day; Den, denervated; DT, dystonin-deficient; kDa, kilodalton; PCR, bility (Sutherland et al., 2005; Bonnal et al., 2008; Fushimi et al., 2008; polymerase chain reaction; PND, post natal day; RBM, RNA Binding Motif; WT, wild-type. Jin et al., 2012; O'Leary et al., 2009; Sugliani et al., 2010; Wang et al., ⁎ Corresponding author at: AMRIC, Health Sciences North, 41 Ramsey Lake Road, Sudbury, ON P3E 5J1, Canada. 2013). Both RBM5 and RBM10 function to modulate apoptosis E-mail address: [email protected] (L.C. Sutherland). (Sutherland et al., 2000, 2005; Mourtada-Maarabouni et al., 2003; http://dx.doi.org/10.1016/j.gene.2015.12.070 0378-1119/© 2016 Elsevier B.V. All rights reserved. B. Ozuemba et al. / Gene 580 (2016) 26–36 27 Rintala-Maki and Sutherland, 2004; Wang et al., 2012; Oh et al., 2006). primary tissues, a myoblast differentiation model and hind limb skeletal Overexpression of exogenous RBM5 has also been shown to cause cell muscle from denervated and from dystonin-deficient mice. Our finding cycle arrest (Mourtada-Maarabouni et al., 2003; Oh et al., 2006). The of ubiquitous but tissue-, development- and disease-specific expression mRNA targets thus far identified for RBM5 encode the apoptosis modu- levels of Rbm5 and Rbm10 suggests that both genes play a necessary role lators CASP2 (Fushimi et al., 2008), FAS and FLICE (Bonnal et al., 2008), in all of the mouse cells examined, and that a mouse model would the deaminase AID (Jin et al., 2012), the cytoskeletal protein therefore be a useful tool for the study of functional consequences of DYSTROPHIN (O'Leary et al., 2009) and 11 spermatid developmental changes in their expression. As a consequence, our data provide a plat- regulators (O'Bryan et al., 2013). The mRNA targets thus far identified form for directed, Rbm5 and Rbm10 variant-specific functional studies for RBM10 encode the apoptosis modulator AT1 (Mueller et al., 2009) relating to myoblast differentiation, muscular atrophy and dystonin- and a number of developmental regulators associated with TARP syn- deficiency. drome (Wang et al., 2013). Thus far, RBM5 has been found to be expressed in a developmental 2. Materials and methods and tissue-specific manner. In general, higher levels are associated with reduced proliferation (consistent with a function that promotes cell 2.1. Animal work cycle arrest and apoptosis). For instance, in normal fibroblast cell lines and lymphocyte cultures, higher expression levels of RBM5 mRNA were All of the protocols pertaining to the procurement of mice tissue observed in samples collected from older versus younger people (Geigl samples were approved by the Laurentian University Animal Care et al., 2004) and in adult versus fetal thymus (Drabkin et al., 1999). Committee and followed stringent animal ethics guidelines (Canadian During seed maturation, expression of the RBM5 plant homolog Suppres- Council on Animal Care). All mice were strain CD1, purchased from sor of ABI3 (SUA) increased as dormancy was induced (Sugliani et al., the Charles River Laboratories (Saint-Constant, QC, Canada). For devel- 2010). RBM5 mRNA and variants encoding RBM5 + 5 + 6 and the anti- opmental and tissue-specific expression analyses in normal mouse tis- sense non-coding RBM5 AS1 (previously termed LUST) were higher in sues (brain, skin, cardiac and skeletal muscle), samples were excised muscle (heart and skeletal) and pancreas (Rintala-Maki and Sutherland, from Post Natal Day (PND) 7 and 14 mice. For expression analyses in 2009), demonstrating either tissue-specific or tissue-restricted (in the disease models, hind limb skeletal muscle was excised from two case of RBM5 AS1)expression.RBM5 was upregulated in drug resistant week-old (PND 14) dystonia musculorum (dtTg4) mice (Kothary et al., cancer cells that had undergone cell cycle arrest and experienced a 1988; Boyer et al., 2010) and wild type (wt) counterparts, and from 7- slow growth rate (Wang et al., 2004), and overexpressed RBM5 retarded day denervated (den) and sham-operated two month-old mice (Boyer tumor growth (Oh et al., 2006; Oh et al., 2002). On the other hand, re- et al., 2014). The denervation procedure was carried out by severing duced expression of RBM5 was observed in highly proliferating cells the hind limb sciatic nerve, and the sham-procedure was performed such as lung cancers, vestibular schwannomas and pancreatic ductal ad- by exposing the sciatic nerve without severing it, as previously de- enocarcinomas (Mourtada-Maarabouni et al., 2003; Oh et al., 2002; scribed (Boyer et al., 2014). Refer to Supplementary Table 1 for a break- Rintala-Maki et al., 2007; Welling et al., 2002; Peng et al., 2013), and down of experimental mouse tissue used. was one component of the 17-gene expression signature associated with solid tumor metastases in humans and mice (Ramaswamy et al., 2.2. Cell culture and differentiation 2003; Qiu et al., 2004). Far less is known about the expression of the RBM5 paralogue C2C12 and H9c2 cells were purchased from ATCC. Culture and differ- RBM10. Two predominant isoforms, RBM10v1 and RBM10v2, differing entiation were carried out as previously described (Masilamani et al., by a single 77 amino acid exon, are encoded by the human RBM10 2014; Menard et al., 1999). All cell culture medium, supplements and gene (Sutherland et al., 2005). A considerably smaller RBM10 isoform, reagents were purchased from Life Technologies (Burlington, ON, we refer to in humans as RBM10v3, has also been reported in GenBank Canada). (Accession Number AK000962.1). Often, data concerning RBM10 ex- pression and function are restricted to RBM10v1. For instance, RBM10 2.3. RNA extraction was expressed in mid-gestation mouse embryos in the brachial arches and limbs (Johnston et al., 2010): nonsense or null mutations led to de- Total RNA extraction from brain, skin, cardiac and skeletal muscle velopmental anomalies, suggesting a key role during early embryogen- from CD1 mice and from wt, dt, sham and den hind limb muscles was esis (Johnston et al., 2010). Experimentally overexpressed RBM10 performed using the Qiagen RNeasy Kit (Qiagen, Mississauga, ON, increased apoptosis and reduced proliferation in rat vascular smooth Canada). Total RNA extraction from C2C12 cells was performed using muscle cells (Mueller et al., 2009).
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