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Loss of Mob1a/B in Mice Results in Chondrodysplasia Due to YAP1/TAZ

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Loss of Mob1a/B in Mice Results in Chondrodysplasia Due to YAP1/TAZ © 2018. Published by The Company of Biologists Ltd | Development (2018) 145, dev159244. doi:10.1242/dev.159244 RESEARCH ARTICLE Loss of Mob1a/b in mice results in chondrodysplasia due to YAP1/ TAZ-TEAD-dependent repression of SOX9 Hiroki Goto1,2,*, Miki Nishio1,2,*, Yoko To1, Tatsuya Oishi1, Yosuke Miyachi1,2, Tomohiko Maehama2, Hiroshi Nishina3, Haruhiko Akiyama4, Tak Wah Mak5, Yuma Makii6, Taku Saito6, Akihiro Yasoda7, Noriyuki Tsumaki8 and Akira Suzuki1,2,‡ ABSTRACT differentiation into resting chondrocytes, followed by the Hippo signaling is modulated in response to cell density, external proliferation of the chondrocytes and their maturation into mechanical forces, and rigidity of the extracellular matrix (ECM). The prehyperplastic and finally hypertrophic chondrocytes (Kronenberg, Mps one binder kinase activator (MOB) adaptor proteins are core 2003; Michigami, 2013). Eventually, these terminally differentiated components of Hippo signaling and influence Yes-associated protein 1 chondrocytes undergo apoptosis during endochondral ossification, (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ), leaving a cartilaginous matrix that becomes mineralized and replaced which are potent transcriptional regulators. YAP1/TAZ are key with bone. The processes of chondrogenesis and endochondral contributors to cartilage and bone development but the molecular ossification are tightly regulated by multiple entities, including mechanisms by which the Hippo pathway controls chondrogenesis transcription factors, growth factors, morphogens and hormones are largely unknown. Cartilage is rich in ECM and also subject to (Melrose et al., 2016). strong external forces – two upstream factors regulating Hippo signaling. Among the transcription factors involved in chondrogenesis and Chondrogenesis and endochondral ossification are tightly controlled endochondral ossification is SOX9. In fact, SOX9, which is a by growth factors, morphogens, hormones, and transcriptional factors member of the Sry-related high mobility group box (SOX) family, is that engage in crosstalk with Hippo-YAP1/TAZ signaling. Here, we an indispensable master regulator of chondrogenesis (Bi et al., 1999; generated tamoxifen-inducible, chondrocyte-specific Mob1a/b-deficient Akiyama, 2008; Lefebvre et al., 1998). In humans, heterozygous mice and show that hyperactivation of endogenous YAP1/TAZ impairs mutations of the SOX9 gene lead to campomelic dysplasia, which is chondrocyte proliferation and differentiation/maturation, leading to characterized by severe skeletal malformation (Wagner et al., 1994). chondrodysplasia. These defects were linked to suppression of SOX9, Supporting evidence provided by mouse models has revealed that a master regulator of chondrogenesis, the expression of which is loss of Sox9 results in hypoplastic cartilage (Akiyama et al., 2002). mediated by TEAD transcription factors. Our data indicate that a MOB1- At the molecular level, SOX9 interacts cooperatively with SOX5 dependent YAP1/TAZ-TEAD complex functions as a transcriptional and SOX6 to drive chondrocyte proliferation and differentiation repressor of SOX9 and thereby negatively regulates chondrogenesis. (Lefebvre et al., 1998; Akiyama et al., 2002; Smits et al., 2001; Ikeda et al., 2004). Other signaling pathways involving fibroblast KEY WORDS: MOB1, YAP1, TAZ, WWTR1, SOX9, Chondrocytes, growth factors (FGFs) (Ornitz, 2005), bone morphogenetic proteins Chondrodysplasia, Mouse (BMPs) (Tsuji et al., 2006), parathyroid hormone (Ellegaard et al., 2010), Indian hedgehog (IHH) (Vortkamp et al., 1996) and WNT/β- INTRODUCTION catenin (Huang et al., 2012) are also key players in chondrocyte Chondrogenesis and endochondral ossification are key contributors differentiation during skeletal development. to the development of the vertebral skeleton. During chondrogenesis, Hippo signaling is modulated in response to cell density, external mesenchymal stem cells (MSCs) undergo condensation and mechanical forces, and rigidity of the extracellular matrix (ECM) (Edgar, 2006; Nishio et al., 2013). The core components of the Hippo pathway are the mammalian STE20-like protein (MST) kinases 1Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan. 2Division of Molecular and Cellular Biology, Kobe (Creasy and Chernoff, 1995), the large tumor suppressor homolog University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan. (LATS) kinases (Tao et al., 1999), and the adaptor proteins salvador 3Department of Developmental and Regenerative Biology, Medical Research homolog 1 (SAV1) (Valverde, 2000) and Mps one binder kinase Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan. 4Department of Orthopaedic Surgery, Gifu University School of Medicine, Gifu 501- activator 1 (MOB1) (Moreno et al., 2001). MOB1A/B are the adaptor 1194, Japan. 5Campbell Family Institute for Breast Cancer Research at the Princess proteins for the LATS kinases. By binding to LATS kinases, Margaret Cancer Centre, University Health Network, Toronto M5G 2C1, Canada; Department of Medical Biophysics, University of Toronto, University Health MOB1A/B strongly increase the kinase activities of these enzymes Network, Toronto M5G 2C1, Canada. 6Department of Sensory and Motor System (Moreno et al., 2001). Activated LATS kinases in turn phosphorylate Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan. Yes-associated protein 1 (YAP1) and transcriptional co-activator with 7Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan. 8Department of Cell Growth and PDZ-binding motif (TAZ; also known as WWTR1) (Sudol, 1994; Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kanai et al., 2000). YAP1/TAZ are key downstream transcriptional Kyoto 606-8507, Japan. co-factors that act mainly on TEA domain transcription factors *These authors contributed equally to this work (TEADs) to regulate numerous target genes involved in cell growth ‡Author for correspondence ([email protected]) and differentiation (Zhao et al., 2008). After phosphorylation by LATS kinases, YAP1/TAZ are excluded from the nucleus Y.T., 0000-0002-7980-7186; T.O., 0000-0002-0371-1866; A.S., 0000-0002- 5950-8808 and retained in the cytoplasm, where they are ubiquitylated by E3-ubiquitin ligase SCFβTRCP (also known as BTRC) and subjected Received 13 September 2017; Accepted 19 February 2018 to proteasome-mediated degradation (Zhao et al., 2010). Thus, in DEVELOPMENT 1 RESEARCH ARTICLE Development (2018) 145, dev159244. doi:10.1242/dev.159244 most cell types, YAP1/TAZ are essentially positive regulators of cell reduction in body size at postnatal day (P) 84 compared with proliferation that are negatively controlled by upstream Hippo core littermate controls (Mob1aflox/flox; Mob1b−/−) (Fig. 1A). components. To study the roles of MOB1A/B during postnatal YAP1/TAZ are considered to be key factors in the regulation of chondrogenesis, we measured the lengths of the long bones and MSC lineage commitment. Under the control of SOX2, YAP1 the size of the cartilaginous growth plates in control and cMob1 maintains MSC self-renewal and inhibits osteogenic differentiation DKO mice at P84. Compared with controls, mutants with Mob1a/b (Seo et al., 2013). However, some studies have reported that low deficiency in chondrocytes showed significant decreases in total TAZ expression promotes adipogenesis, whereas high TAZ levels body length as well as in the length of the femur, tibia, humerus and drive osteogenesis (Hong et al., 2005; Cui et al., 2003; Yang et al., forelimb (Fig. 1B). The size of the articular cartilage layer was also 2013). Thus, the functions and molecular mechanisms by which decreased in the mutants at P12 (Fig. 1C). Close histological YAP1/TAZ influence mesenchymal cells are complicated and examination of growth plates at P21 revealed that each chondrocyte remain largely unknown. It is clear that cartilage is rich in ECM and zone (resting, proliferative, and hypertrophic) was present in cMob1 also subject to strong external forces, both of which are important DKO mice but proportionally reduced in size compared with that in upstream regulators of Hippo-YAP1/TAZ signaling. In addition, control animals (Fig. 1D). Thus, loss of Mob1a/b in chondrocytes Hippo-YAP1/TAZ signaling has been shown to engage in crosstalk results in chondrodysplasia. with FGFs (Rizvi et al., 2016), BMPs (Alarcón et al., 2009), IHH (Wang et al., 2016), WNT/β-catenin (Varelas et al., 2010), SOX2 MOB1A/B deficiency in chondrocytes impairs their (Lian et al., 2010) and SOX9 (Song et al., 2014), all of which proliferation and differentiation are crucial for chondrogenesis. Nevertheless, the molecular Because cMob1 DKO mice exhibited abnormal histology in their mechanisms by which Hippo-YAP1/TAZ signaling controls growth plate cartilage, we analyzed the proliferation and chondrocyte generation and homeostasis remain unclear. differentiation of chondrocytes. Histological examination of control Col2a1-Yap1 transgenic mice were recently reported to display and mutant growth plates at P21 using PCNA staining to identify increased early chondrocyte proliferation driven by YAP1/TEAD- proliferating cells revealed that many PCNA-positive cells were dependent SOX6 activation, but also exhibited YAP1/RUNX2- present in control growth plates (as expected), especially in the dependent COL10A1 inhibition, impaired chondrocyte maturation proliferative
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