Common and Distinctive Functions of the Hippo Effectors Taz and Yap in Skeletal Muscle Stem Cell Function

Abstract

Hippo pathway downstream effectors Yap and Taz play key roles in cell proliferation and regeneration, regulating gene expression especially via Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analyzed Taz in vivo and ex vivo in comparison with Yap. Small interfering RNA knockdown or retroviral‐mediated expression of wild‐type human or constitutively active TAZ mutants in satellite cells showed that TAZ promoted proliferation, a function shared with YAP. However, at later stages of myogenesis, TAZ also enhanced myogenic differentiation of myoblasts, whereas YAP inhibits such differentiation. Functionally, while muscle growth was mildly affected in Taz (gene Wwtr1 –/–) knockout mice, there were no overt effects on regeneration. Conversely, conditional knockout of Yap in satellite cells of Pax7Cre‐ERT2/+: Yapfl°x/fl°x:Rosa26Lacz mice produced a regeneration deficit. To identify potential mechanisms, microarray analysis showed many common TAZ/YAP target genes, but TAZ also regulates some genes independently of YAP, including myogenic genes such as Pax7, Myf5, and Myod1 (ArrayExpress–E‐MTAB‐5395). Proteomic analysis revealed many novel binding partners of TAZ/YAP in myogenic cells, but TAZ also interacts with proteins distinct from YAP that are often involved in myogenesis and aspects of cytoskeleton organization (ProteomeXchange–PXD005751). Neither TAZ nor YAP bind members of the Wnt destruction complex but both regulated expression of Wnt and Wnt‐cross talking genes with known roles in myogenesis. Finally, TAZ operates through Tead4 to enhance myogenic differentiation. In summary, Taz and Yap have overlapping functions in promoting myoblast proliferation but Taz then switches to enhance myogenic differentiation. Stem Cells 2017;35:1958–1972

Verteporfin targeting YAP1/TAZ‐TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells

“…YAP1 and TAZ are paralogue genes which display redundant effects in terms of molecular activity but may exert divergent roles in development. 29 We also showed that the number of CD44+ cells increased after conventional chemotherapies. Their chemoresistance may involve multiple mechanisms.…”

“…Unlike YAP1 , TAZ was not significantly overexpressed in CD44+ cells compared to CD44− cells, although it was also associated with a reduced overall survival of nonmetastatic GC patients. YAP1 and TAZ are paralogue genes which display redundant effects in terms of molecular activity but may exert divergent roles in development …”

Acute environmental hypoxia potentiates satellite cell‐dependent myogenesis in response to resistance exercise through the inflammation pathway in human

“…Dephosphorylation of YAP at Ser127is known to promote its nuclear translocation and its activation. 12 Thus, our results suggest that YAP could be involved in resistance exercise-induced satellite cell activation and proliferation independent of O 2 conditions. Similar results were found for TAZ targets, which were regulated by exercise but not by hypoxia, with the exception of pmp22.…”

“…6 Resistance training is a well-known strategy to induce skeletal muscle hypertrophy notably through protein synthesis activation, proteolysis inhibition, and activation of the myogenic program. [8][9][10][11][12][13] Although chronic hypoxia induces skeletal muscle wasting, 14 intermittent hypoxia has recently been identified as an efficient stimulus to promote satellite cell proliferation and muscle protein accretion. [8][9][10][11][12][13] Although chronic hypoxia induces skeletal muscle wasting, 14 intermittent hypoxia has recently been identified as an efficient stimulus to promote satellite cell proliferation and muscle protein accretion.…”

“…[26][27][28] Mechanistically, IL-6 is responsible for STAT3 translocation in the nucleus. 12 While YAP promotes satellite cell activation, migration, and proliferation, TAZ is responsible for muscle satellite cell differentiation and fusion. [29][30][31][32] The Hippo pathway fosters myogenesis through its two effectors, yes associated protein (YAP) and tafazzin (TAZ) transcription factors.…”