TGFβ signaling is critical for maintenance of the tendon cell fate

Guak Kim Tan; Brian A. Pryce; Anna Stabio; John V. Brigande; Chaojie Wang; Zheng Xia; Sara F. Tufa; Douglas R. Keene; Ronen Schweitzer

doi:10.7554/eLife.52695

TGFβ signaling is critical for maintenance of the tendon cell fate

Guak Kim Tan, Brian A. Pryce, Anna Stabio, John V. Brigande, Chaojie Wang, Zheng Xia, Sara F. Tufa, Douglas R. Keene, Ronen Schweitzer

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44 Scopus citations

Abstract

Studies of cell fate focus on specification, but little is known about maintenance of the differentiated state. In this study we find that the mouse tendon cell fate requires continuous maintenance in vivo and identify an essential role for TGFβ signaling in maintenance of the tendon cell fate. To examine the role of TGFβ signaling in tenocyte function the TGFβ type II receptor (Tgfbr2) was targeted in the Scleraxis-expressing cell lineage using the ScxCre deletor. Tendon development was not disrupted in mutant embryos, but shortly after birth tenocytes lost differentiation markers and reverted to a more stem/progenitor state. Viral reintroduction of Tgfbr2 to mutants prevented and even rescued tenocyte dedifferentiation suggesting a continuous and cell autonomous role for TGFβ signaling in cell fate maintenance. These results uncover the critical importance of molecular pathways that maintain the differentiated cell fate and a key role for TGFβ signaling in these processes.

Original language	English (US)
Article number	e52695
Journal	eLife
Volume	9
DOIs	https://doi.org/10.7554/eLife.52695
State	Published - Jan 2020

ASJC Scopus subject areas

Neuroscience(all)
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)

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10.7554/eLife.52695

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title = "TGFβ signaling is critical for maintenance of the tendon cell fate",

abstract = "Studies of cell fate focus on specification, but little is known about maintenance of the differentiated state. In this study we find that the mouse tendon cell fate requires continuous maintenance in vivo and identify an essential role for TGFβ signaling in maintenance of the tendon cell fate. To examine the role of TGFβ signaling in tenocyte function the TGFβ type II receptor (Tgfbr2) was targeted in the Scleraxis-expressing cell lineage using the ScxCre deletor. Tendon development was not disrupted in mutant embryos, but shortly after birth tenocytes lost differentiation markers and reverted to a more stem/progenitor state. Viral reintroduction of Tgfbr2 to mutants prevented and even rescued tenocyte dedifferentiation suggesting a continuous and cell autonomous role for TGFβ signaling in cell fate maintenance. These results uncover the critical importance of molecular pathways that maintain the differentiated cell fate and a key role for TGFβ signaling in these processes.",

author = "Tan, {Guak Kim} and Pryce, {Brian A.} and Anna Stabio and Brigande, {John V.} and Chaojie Wang and Zheng Xia and Tufa, {Sara F.} and Keene, {Douglas R.} and Ronen Schweitzer",

note = "Funding Information: The authors thank Dr Elazar Zelzer (Department of Molecular Genetics, Weizmann Institute of Science, Israel) for critical reading of the manuscript. We are grateful to staff from MPSSR and FACS core facilities, OHSU particularly Dr Robert Searles, Mrs Amy Carlos and Dr Miranda Gilchrist for their excellent technical assistance. This work was funded by NIH (R01AR055973, RS; R01DC014160, JVB) and Shriners Hospitals for Children (SHC 5410-POR-14). G.K.T was supported by Research Fellowship from Shriners Hospital for Children. Funding Information: Gilchrist for their excellent technical assistance. This work was funded by NIH (R01AR055973, RS; R01DC014160, JVB) and Shriners Hospitals for Children (SHC 5410-POR-14). G.K.T was supported by Research Fellowship from Shriners Hospital for Children. Publisher Copyright: {\textcopyright} 2020, eLife Sciences Publications Ltd. All rights reserved.",

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AU - Pryce, Brian A.

AU - Stabio, Anna

AU - Brigande, John V.

AU - Wang, Chaojie

AU - Xia, Zheng

AU - Tufa, Sara F.

AU - Keene, Douglas R.

AU - Schweitzer, Ronen

N1 - Funding Information: The authors thank Dr Elazar Zelzer (Department of Molecular Genetics, Weizmann Institute of Science, Israel) for critical reading of the manuscript. We are grateful to staff from MPSSR and FACS core facilities, OHSU particularly Dr Robert Searles, Mrs Amy Carlos and Dr Miranda Gilchrist for their excellent technical assistance. This work was funded by NIH (R01AR055973, RS; R01DC014160, JVB) and Shriners Hospitals for Children (SHC 5410-POR-14). G.K.T was supported by Research Fellowship from Shriners Hospital for Children. Funding Information: Gilchrist for their excellent technical assistance. This work was funded by NIH (R01AR055973, RS; R01DC014160, JVB) and Shriners Hospitals for Children (SHC 5410-POR-14). G.K.T was supported by Research Fellowship from Shriners Hospital for Children. Publisher Copyright: © 2020, eLife Sciences Publications Ltd. All rights reserved.

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N2 - Studies of cell fate focus on specification, but little is known about maintenance of the differentiated state. In this study we find that the mouse tendon cell fate requires continuous maintenance in vivo and identify an essential role for TGFβ signaling in maintenance of the tendon cell fate. To examine the role of TGFβ signaling in tenocyte function the TGFβ type II receptor (Tgfbr2) was targeted in the Scleraxis-expressing cell lineage using the ScxCre deletor. Tendon development was not disrupted in mutant embryos, but shortly after birth tenocytes lost differentiation markers and reverted to a more stem/progenitor state. Viral reintroduction of Tgfbr2 to mutants prevented and even rescued tenocyte dedifferentiation suggesting a continuous and cell autonomous role for TGFβ signaling in cell fate maintenance. These results uncover the critical importance of molecular pathways that maintain the differentiated cell fate and a key role for TGFβ signaling in these processes.

AB - Studies of cell fate focus on specification, but little is known about maintenance of the differentiated state. In this study we find that the mouse tendon cell fate requires continuous maintenance in vivo and identify an essential role for TGFβ signaling in maintenance of the tendon cell fate. To examine the role of TGFβ signaling in tenocyte function the TGFβ type II receptor (Tgfbr2) was targeted in the Scleraxis-expressing cell lineage using the ScxCre deletor. Tendon development was not disrupted in mutant embryos, but shortly after birth tenocytes lost differentiation markers and reverted to a more stem/progenitor state. Viral reintroduction of Tgfbr2 to mutants prevented and even rescued tenocyte dedifferentiation suggesting a continuous and cell autonomous role for TGFβ signaling in cell fate maintenance. These results uncover the critical importance of molecular pathways that maintain the differentiated cell fate and a key role for TGFβ signaling in these processes.

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TGFβ signaling is critical for maintenance of the tendon cell fate

Abstract

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