Control of skeletal morphogenesis by the Hippo-YAP/TAZ pathway

Abstract

The Hippo-YAP/TAZ pathway is an important regulator of tissue growth, but can also control cell fate or tissue morphogenesis. Here we investigate the function of the Hippo pathway during the development of cartilage, which forms the majority of the skeleton. Previously, YAP was proposed to inhibit skeletal size by repressing chondrocyte proliferation and differentiation. We find that, in vitro, Yap/Taz double knockout impairs chondrocyte proliferation, whilst constitutively nuclear nls-YAP5SA accelerates proliferation, in line with the canonical role of this pathway in most tissues. However, in vivo, cartilage-specific knockout of Yap/Taz does not prevent chondrocyte proliferation, differentiation, or skeletal growth, but rather results in various skeletal deformities including cleft palate. Cartilage-specific expression of nls-YAP5SA or knockout of Lats1/2 do not increase cartilage growth but instead lead to catastrophic malformations resembling chondrodysplasia or achondrogenesis. Physiological YAP target genes in cartilage include Ctgf, Cyr61 and several matrix remodelling enzymes. Thus, YAP/TAZ activity controls chondrocyte proliferation in vitro, possibly reflecting a regenerative response, but is dispensable for chondrocyte proliferation in vivo, and instead functions to control cartilage morphogenesis via regulation of the extracellular matrix.

ASCL1 represses a SOX9+ neural crest stem-like state in small cell lung cancer

“…During development, both MSC and NC-stem-like progenitors have the capacity for bone development given the appropriate developmental signals. Multiple developmental pathways are known to drive bone fate including Indian hedgehog (Ihh), Hippo/Yap1, Transforming growth factor-β (Tgfβ), Bone morphogenic protein (Bmp), Wnt, Notch, and others (Long 2012;Pan et al 2018;Vanyai et al 2020). Numerous components of these pathways were transcriptionally up-regulated in RPMA tumors including Ihh, Yap1, Bmp family members (Bmp3, Bmp5, Bmp2k, Bmp8a, and Bmpr2), Tgfβ receptors (Tgfbr2 and Tgfbr3), Smads (Smad3, Smad6, and Smad7), Wnt ligands (Wnt2, Wnt2b, Wnt3a, Wnt5a, Wnt6, Wnt7b, Wnt10a, and Wnt10b), and Notch receptors and target genes (Notch1, Notch2, Hes1, and Rest) (Fig.…”

YAP/TAZ in Bone and Cartilage Biology

“…Overexpression of YAP/TAZ in chondrocytes induced by MOB1A/B and constitutive activation of YAP in cartilage resulted in a phenotype of chondrodysplasia ( Table 3 ) ( Goto et al, 2018 ; Vanyai et al, 2020 ). MOB1A/B deletion in mice revealed a low growth plate length and long bones, associated with altered proliferation, differentiation, and endochondral ossification.…”

“…Recently, Vanyai and collaborators demonstrated that YAP/TAZ conditional deletion in chondrocytes from Col2a1 Cre mice (Yap fl/fl ; Tazfl /fl ; Col2a1 Cre+ ) resulted in neonatal lethality due in part to a cleft palate ( Vanyai et al, 2020 ). The authors highlighted the phenotype inconsistency between in vitro and in vivo because YAP/TAZ are not required for cell proliferation in the cartilage growth plate in vivo .…”

ADAMTS5 in Osteoarthritis: Biological Functions, Regulatory Network, and Potential Targeting Therapies

“…Yes-Associated Protein/TAZ Signaling Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling are important not only for mediating tissue growth, cell fate, and tissue morphogenesis but also in the development of cartilage (Vanyai et al, 2020). YAP signaling is regulated by upstream Hippo-dependent and independent signaling, such as mechanical cues, metabolic signals, and other signaling pathways (Dupont, 2016).…”

“…While inhibition of YAP expression can ameliorate osteoarthritic cartilage degradation, other studies have revealed that YAP plays a protective role as an inflammatory inhibitor in the progression of OA ( Deng et al, 2018 ). In addition, both Yap knockout and overexpression of YAP promote cartilage disruption, indicating that YAP regulates cartilage homeostasis in a biphasic manner ( Deng et al, 2018 ; Zhang et al, 2019 ; Vanyai et al, 2020 ).…”