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Wnt/Β-Catenin Signaling Via Axin2 Is Required for Myogenesis And

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Wnt/Β-Catenin Signaling Via Axin2 Is Required for Myogenesis And © 2016. Published by The Company of Biologists Ltd | Development (2016) 143, 3128-3142 doi:10.1242/dev.139907 RESEARCH ARTICLE Wnt/β-catenin signaling via Axin2 is required for myogenesis and, together with YAP/Taz and Tead1, active in IIa/IIx muscle fibers Danyil Huraskin1,‡, Nane Eiber1,‡, Martin Reichel2,*, Laura M. Zidek3, Bojana Kravic1, Dominic Bernkopf2, Julia von Maltzahn3,Jürgen Behrens2 and Said Hashemolhosseini1,¶ ABSTRACT are expressed in the dorsal ectoderm, and Wnt11 is expressed in the Canonical Wnt/β-catenin signaling plays an important role in epaxial dermomyotome. In adult muscle, Wnt proteins are expressed myogenic differentiation, but its physiological role in muscle fibers upon regeneration (Polesskaya et al., 2003; von Maltzahn et al., remains elusive. Here, we studied activation of Wnt/β-catenin 2012). Non-canonical Wnt signaling through Wnt7a regulates signaling in adult muscle fibers and muscle stem cells in an Axin2 satellite cell number and the size of skeletal muscle (Le Grand et al., reporter mouse. Axin2 is a negative regulator and a target of Wnt/β- 2009; von Maltzahn et al., 2013). Generally, non-canonical Wnt catenin signaling. In adult muscle fibers, Wnt/β-catenin signaling is signaling is required for skeletal muscle development, while only detectable in a subset of fast fibers that have a significantly canonical Wnt signaling, especially via Wnt3a, has been smaller diameter than other fast fibers. In the same fibers, demonstrated to lead to increased fibrosis (Brack et al., 2007). immunofluorescence staining for YAP/Taz and Tead1 was In canonical Wnt signaling the Wnt binds to the Fzd and Lrp5/6 detected. Wnt/β-catenin signaling was absent in quiescent and receptor pairs, thereby leading to the inactivation of glycogen β β activated satellite cells. Upon injury, Wnt/β-catenin signaling was synthase kinase 3 (GSK3 ) through dishevelled (Dsh). In the β detected in muscle fibers with centrally located nuclei. During absence of Wnt stimulation, -catenin forms a destruction complex β differentiation of myoblasts expression of Axin2, but not of Axin1, with adenomatosis polyposis coli (APC), Axin1 and GSK3 β increased together with Tead1 target gene expression. Furthermore, (MacDonald et al., 2009). Phosphorylation of -catenin by casein β absence of Axin1 and Axin2 interfered with myoblast proliferation and kinase I (CK1) and GSK3 causes ubiquitylation and proteasome- β myotube formation, respectively. Treatment with the canonical Wnt3a mediated degradation of -catenin. The presence of Wnt ligand ligand also inhibited myotube formation. Wnt3a activated TOPflash results in the activation of Dsh, which leads to phosphorylation- and Tead1 reporter activity, whereas neither reporter was activated in dependent recruitment of Axin1 to the low-density lipoprotein the presence of Dkk1, an inhibitor of canonical Wnt signaling. We receptor-related protein (LRP) receptor and disassembly of the β β propose that Axin2-dependent Wnt/β-catenin signaling is involved in -catenin degradation complex. Stabilized -catenin accumulates in myotube formation and, together with YAP/Taz/Tead1, associated the cytoplasm and translocates to the nucleus. There, it complexes with reduced muscle fiber diameter of a subset of fast fibers. with T cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors and acts as a transcriptional coactivator to KEY WORDS: Axin2, Yap1, Wwtr1, Tead1, Skeletal muscle, induce the context-dependent expression of Wnt/β-catenin target Muscle fibers, Satellite cells genes (Eastman and Grosschedl, 1999). In contrast to canonical Wnt signaling, non-canonical Wnt signaling does not require the activity INTRODUCTION of β-catenin. Examples of non-canonical Wnt signaling pathways in The Wnt gene family encodes 19 secreted glycoproteins, which bind skeletal muscle are the planar cell polarity (PCP) and the to the Frizzled (Fzd) transmembrane receptors on target cells. Wnt AKT/mTOR (Bentzinger et al., 2014; Le Grand et al., 2009; von proteins regulate key processes such as development and Maltzahn et al., 2013) pathways. differentiation (Bhanot et al., 1996; Cadigan and Nusse, 1997; Mechanical load or training can lead to an increase of myofiber Clevers, 2006; von Maltzahn et al., 2012) and are fundamental size, accompanied by muscle enlargement. This condition is called during embryonic myogenesis (von Maltzahn et al., 2012). For hypertrophy and multiple studies identified different roles for instance, they regulate the development of embryonic muscle in a canonical and non-canonical Wnt signaling in muscle fiber spatiotemporal manner. Wnt1, Wnt3a and Wnt4 are expressed in the hypertrophy (Armstrong and Esser, 2005; Bernardi et al., 2011; dorsal regions of the neural tube, whereas Wnt4, Wnt6 and Wnt7a Han et al., 2011; Rochat et al., 2004; von Maltzahn et al., 2011). Furthermore, expression of β-catenin is a prerequisite for the 1Institute of Biochemistry, Fahrstrasse 17, Friedrich-Alexander University Erlangen- physiological growth of adult skeletal muscle, underscoring the Nürnberg, Erlangen D-91054, Germany. 2Nikolaus-Fiebiger-Center of Molecular importance of canonical Wnt signaling (Armstrong et al., 2006). A Medicine, Glückstrasse 6, Friedrich-Alexander University Erlangen-Nürnberg, recent study employed TCF reporter mice to gain further insights Erlangen D-91054, Germany. 3Leibniz Institute for Age Research/Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, Jena D-07745, Germany. into the role of canonical Wnt signaling (Kuroda et al., 2013). They *Present address: Department of Psychiatry and Psychotherapy, found that canonical Wnt signaling is strongly activated during fetal Schwabachanlage 6, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen myogenesis and only weakly activated in adult muscles, where it is D-91054, Germany. ‡ These authors contributed equally to this work limited to slow myofibers. Their data suggest that canonical Wnt signaling promotes the formation of, or switch to, slow fiber types ¶ Author for correspondence ([email protected]) and inhibits myogenesis (Kuroda et al., 2013). Furthermore, they S.H., 0000-0002-6564-5649 demonstrated that Wnt1 and Wnt3a are potent activators of canonical Wnt signaling in myogenic progenitors using a Received 22 May 2016; Accepted 13 July 2016 TCF-luciferase reporter assay. DEVELOPMENT 3128 RESEARCH ARTICLE Development (2016) 143, 3128-3142 doi:10.1242/dev.139907 Axin1 and Axin2 are closely related (∼45% amino acid identity) prominently, in multi-nucleated myotubes (Fig. 1A). To follow the negative regulators of canonical Wnt signaling (Behrens et al., temporal expression profile and protein expression of Axin1 and 1998; Zeng et al., 1997). They have similar biochemical and cell Axin2, proliferating C2C12 myoblasts and differentiating myotubes biological properties but may differ in their in vivo functions. were analyzed by immunoblot. Axin1 appeared to be constitutively Whereas Axin1 is homogenously distributed in the mouse embryo expressed, whereas Axin2 protein was not detectable in myoblasts (Zeng et al., 1997), Axin2 is a Wnt target gene and more selectively but increased gradually in differentiating myotubes (Fig. 1B,C). expressed in specific tissues (Behrens et al., 1998). Mutant embryos Expression of Axin1 and Axin2 in C2C12 cells was validated by lacking Axin1 die at embryonic day (E) 9.5, with abnormalities quantitative PCR analysis (Fig. 1D). A TOPflash assay showed an including truncation of the forebrain, neural tube defects and increase in β-catenin/TCF-mediated gene transcription upon embryonic axis duplications (Gluecksohn-Schoenheimer, 1949; differentiation (Fig. 1E). Altogether, Axin2 expression and Perry et al., 1995). Mice lacking Axin2 are viable but display β-catenin-mediated canonical Wnt activity increased in craniofacial defects (Lustig et al., 2002; Yu et al., 2005). differentiating myotubes. Interestingly, Axin2 has been shown to be upregulated in C2C12 mouse myoblast cells during differentiation (Bernardi et al., 2011; Expression profile of Axin2 in adult skeletal muscles Figeac and Zammit, 2015). Importantly, no in vivo data on the The importance of canonical Wnt/β-catenin signaling in resting function of Axin2 in skeletal muscle are available so far. adult myofibers in vivo is not known. Therefore, we investigated the Another important pathway involved in the control of organ size, expression profile of Axin2 (using Axin2-lacZ mice) as a reporter tissue regeneration and stem cell self-renewal is the Hippo pathway for canonical Wnt signaling in different adult skeletal muscles. In (Zhao et al., 2011). In mammals, the activation of kinases MST1/2 Axin2-lacZ mice, the lacZ cassette is inserted in frame with the ATG (also known as Stk4/3; homologs of Drosophila Hippo) and start codon of Axin2 and thus β-galactosidase (β-gal) activity LATS1/2 leads to LATS-dependent phosphorylation of Taz (also reflects Axin2 gene expression (Lustig et al., 2002). Diaphragm known as Wwtr1) and YAP (also known as Yap1), thereby muscles of Axin2-lacZ reporter mice were dissected and stained with decreasing their stability, nuclear localization and transcriptional X-Gal (Fig. 2A). As expected, myofibers of diaphragms of wild- activity (Pan, 2010). Recently, YAP was identified as a crucial type littermates did not show any positive staining even after 24 h of regulator of muscle fiber size (Watt et al., 2015). Moreover, YAP/ incubation with X-Gal, whereas many myofibers of heterozygous Taz are incorporated
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