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

Congshan Sun, Vanessa De Mello, Abdalla Mohamed, Huascar P. Ortuste Quiroga, Amaya Garcia-Munoz, Abdullah Al Bloshi, Annie M. Tremblay, Alexander von Kriegsheim, Elaina Collie-Duguid, Neil Vargesson, David Matallanas, Henning Wackerhage, Peter S. Zammit

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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 analysed Taz in vivo and ex vivo in comparison to Yap. siRNA knockdown or retroviral-mediated expression of wildtype 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 marked 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.
Original languageEnglish
Pages (from-to)1958-1972
Number of pages15
JournalStem Cells
Volume35
Issue number8
Early online date27 Jun 2017
DOIs
Publication statusPublished - Aug 2017

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Muscle Cells
Muscle Development
Skeletal Muscle
Stem Cells
Regeneration
Myoblasts
Genes
Gene Knockout Techniques
Microarray Analysis
Cytoskeleton
Knockout Mice
Proteomics
Small Interfering RNA
Transcription Factors
Cell Proliferation
Gene Expression
Muscles
Growth
Proteins

Keywords

  • Taz
  • satellite cells
  • muscle stem cells
  • skeletal muscle
  • Yap
  • adult stem cells
  • cell biology
  • differentiation
  • Tead

Cite this

Sun, C., De Mello, V., Mohamed, A., Quiroga, H. P. O., Garcia-Munoz, A., Al Bloshi, A., ... Zammit, P. S. (2017). Common and Distinctive Functions of the Hippo Effectors Taz and Yap in Skeletal Muscle Stem Cell Function. Stem Cells, 35(8), 1958-1972. https://doi.org/10.1002/stem.2652

Common and Distinctive Functions of the Hippo Effectors Taz and Yap in Skeletal Muscle Stem Cell Function. / Sun, Congshan; De Mello, Vanessa; Mohamed, Abdalla; Quiroga, Huascar P. Ortuste ; Garcia-Munoz, Amaya ; Al Bloshi, Abdullah ; Tremblay, Annie M.; von Kriegsheim, Alexander ; Collie-Duguid, Elaina; Vargesson, Neil; Matallanas, David; Wackerhage, Henning; Zammit, Peter S.

In: Stem Cells, Vol. 35, No. 8, 08.2017, p. 1958-1972.

Research output: Contribution to journalArticle

Sun, C, De Mello, V, Mohamed, A, Quiroga, HPO, Garcia-Munoz, A, Al Bloshi, A, Tremblay, AM, von Kriegsheim, A, Collie-Duguid, E, Vargesson, N, Matallanas, D, Wackerhage, H & Zammit, PS 2017, 'Common and Distinctive Functions of the Hippo Effectors Taz and Yap in Skeletal Muscle Stem Cell Function', Stem Cells, vol. 35, no. 8, pp. 1958-1972. https://doi.org/10.1002/stem.2652
Sun C, De Mello V, Mohamed A, Quiroga HPO, Garcia-Munoz A, Al Bloshi A et al. Common and Distinctive Functions of the Hippo Effectors Taz and Yap in Skeletal Muscle Stem Cell Function. Stem Cells. 2017 Aug;35(8):1958-1972. https://doi.org/10.1002/stem.2652
Sun, Congshan ; De Mello, Vanessa ; Mohamed, Abdalla ; Quiroga, Huascar P. Ortuste ; Garcia-Munoz, Amaya ; Al Bloshi, Abdullah ; Tremblay, Annie M. ; von Kriegsheim, Alexander ; Collie-Duguid, Elaina ; Vargesson, Neil ; Matallanas, David ; Wackerhage, Henning ; Zammit, Peter S. / Common and Distinctive Functions of the Hippo Effectors Taz and Yap in Skeletal Muscle Stem Cell Function. In: Stem Cells. 2017 ; Vol. 35, No. 8. pp. 1958-1972.
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T1 - Common and Distinctive Functions of the Hippo Effectors Taz and Yap in Skeletal Muscle Stem Cell Function

AU - Sun, Congshan

AU - De Mello, Vanessa

AU - Mohamed, Abdalla

AU - Quiroga, Huascar P. Ortuste

AU - Garcia-Munoz, Amaya

AU - Al Bloshi, Abdullah

AU - Tremblay, Annie M.

AU - von Kriegsheim, Alexander

AU - Collie-Duguid, Elaina

AU - Vargesson, Neil

AU - Matallanas, David

AU - Wackerhage, Henning

AU - Zammit, Peter S.

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N2 - 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 analysed Taz in vivo and ex vivo in comparison to Yap. siRNA knockdown or retroviral-mediated expression of wildtype 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 marked 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.

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