The E3 ubiquitin ligase SMURF1 regulates cell-fate specification and outflow tract septation during mammalian heart development

Karen Koefoed Rasmussen; Josephine Skat-Rørdam; P. Andersen; Caroline Becker Warzecha; M. Pye; Troels Askhøj Andersen; Katrine Dalsgaard Ajbro; E. Bendsen; M. Narimatsu; Frederik Vilhardt; Lotte Bang Pedersen; J. L. Wrana; R. H. Anderson; Kjeld Møllgård; Søren Tvorup Christensen; Lars Allan Larsen

doi:10.1038/s41598-018-27854-8

The E3 ubiquitin ligase SMURF1 regulates cell-fate specification and outflow tract septation during mammalian heart development

Karen Koefoed Rasmussen, Josephine Skat-Rørdam, P. Andersen, Caroline Becker Warzecha, M. Pye, Troels Askhøj Andersen, Katrine Dalsgaard Ajbro, E. Bendsen, M. Narimatsu, Frederik Vilhardt, Lotte Bang Pedersen, J. L. Wrana, R. H. Anderson, Kjeld Møllgård, Søren Tvorup Christensen^*, Lars Allan Larsen

^*Corresponding author for this work

7 Citations (Scopus)

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Abstract

Smad ubiquitin regulatory factor 1 (SMURF1) is a HECT-type E3 ubiquitin ligase that plays a critical role in vertebrate development by regulating planar cell polarity (PCP) signaling and convergent extension (CE). Here we show that SMURF1 is involved in mammalian heart development. We find that SMURF1 is highly expressed in outflow tract cushion mesenchyme and Smurf1 ^-/- mouse embryos show delayed outflow tract septation. SMURF1 is expressed in smooth muscle cells of the coronary arteries and great vessels. Thickness of the aortic smooth muscle cell layer is reduced in Smurf1 ^-/- mouse embryos. We show that SMURF1 is a negative regulator of cardiomyogenesis and a positive regulator of smooth muscle cell and cardiac fibroblast differentiation, indicating that SMURF1 is important for cell-type specification during heart development. Finally, we provide evidence that SMURF1 localizes at the primary cilium where it may regulate bone morphogenetic protein (BMP) signaling, which controls the initial phase of cardiomyocyte differentiation. In summary, our results demonstrate that SMURF1 is a critical regulator of outflow tract septation and cell-type specification during heart development, and that these effects may in part be mediated via control of cilium-associated BMP signaling.

Original language	English
Article number	9542
Journal	Scientific Reports
Volume	8
Issue number	1
Number of pages	14
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-018-27854-8
Publication status	Published - 2018

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The E3 ubiquitin ligase SMURF1 regulates cell-fate specification and outflow tract septation during mammalian heart developmentFinal published version, 6.34 MBLicence: CC BY

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Rasmussen, K. K., Skat-Rørdam, J., Andersen, P., Warzecha, C. B., Pye, M., Andersen, T. A., Ajbro, K. D., Bendsen, E., Narimatsu, M., Vilhardt, F., Pedersen, L. B., Wrana, J. L., Anderson, R. H., Møllgård, K., Christensen, S. T., & Larsen, L. A. (2018). The E3 ubiquitin ligase SMURF1 regulates cell-fate specification and outflow tract septation during mammalian heart development. Scientific Reports, 8(1), Article 9542. https://doi.org/10.1038/s41598-018-27854-8

Rasmussen, KK, Skat-Rørdam, J, Andersen, P, Warzecha, CB, Pye, M, Andersen, TA, Ajbro, KD, Bendsen, E, Narimatsu, M, Vilhardt, F , Pedersen, LB, Wrana, JL, Anderson, RH, Møllgård, K , Christensen, ST & Larsen, LA 2018, 'The E3 ubiquitin ligase SMURF1 regulates cell-fate specification and outflow tract septation during mammalian heart development', Scientific Reports, vol. 8, no. 1, 9542. https://doi.org/10.1038/s41598-018-27854-8

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title = "The E3 ubiquitin ligase SMURF1 regulates cell-fate specification and outflow tract septation during mammalian heart development",

abstract = "Smad ubiquitin regulatory factor 1 (SMURF1) is a HECT-type E3 ubiquitin ligase that plays a critical role in vertebrate development by regulating planar cell polarity (PCP) signaling and convergent extension (CE). Here we show that SMURF1 is involved in mammalian heart development. We find that SMURF1 is highly expressed in outflow tract cushion mesenchyme and Smurf1 -/- mouse embryos show delayed outflow tract septation. SMURF1 is expressed in smooth muscle cells of the coronary arteries and great vessels. Thickness of the aortic smooth muscle cell layer is reduced in Smurf1 -/- mouse embryos. We show that SMURF1 is a negative regulator of cardiomyogenesis and a positive regulator of smooth muscle cell and cardiac fibroblast differentiation, indicating that SMURF1 is important for cell-type specification during heart development. Finally, we provide evidence that SMURF1 localizes at the primary cilium where it may regulate bone morphogenetic protein (BMP) signaling, which controls the initial phase of cardiomyocyte differentiation. In summary, our results demonstrate that SMURF1 is a critical regulator of outflow tract septation and cell-type specification during heart development, and that these effects may in part be mediated via control of cilium-associated BMP signaling.",

author = "Rasmussen, {Karen Koefoed} and Josephine Skat-R{\o}rdam and P. Andersen and Warzecha, {Caroline Becker} and M. Pye and Andersen, {Troels Askh{\o}j} and Ajbro, {Katrine Dalsgaard} and E. Bendsen and M. Narimatsu and Frederik Vilhardt and Pedersen, {Lotte Bang} and Wrana, {J. L.} and Anderson, {R. H.} and Kjeld M{\o}llg{\aa}rd and Christensen, {S{\o}ren Tvorup} and Larsen, {Lars Allan}",

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AU - Rasmussen, Karen Koefoed

AU - Skat-Rørdam, Josephine

AU - Andersen, P.

AU - Warzecha, Caroline Becker

AU - Pye, M.

AU - Andersen, Troels Askhøj

AU - Ajbro, Katrine Dalsgaard

AU - Bendsen, E.

AU - Narimatsu, M.

AU - Vilhardt, Frederik

AU - Pedersen, Lotte Bang

AU - Wrana, J. L.

AU - Anderson, R. H.

AU - Møllgård, Kjeld

AU - Christensen, Søren Tvorup

AU - Larsen, Lars Allan

PY - 2018

Y1 - 2018

N2 - Smad ubiquitin regulatory factor 1 (SMURF1) is a HECT-type E3 ubiquitin ligase that plays a critical role in vertebrate development by regulating planar cell polarity (PCP) signaling and convergent extension (CE). Here we show that SMURF1 is involved in mammalian heart development. We find that SMURF1 is highly expressed in outflow tract cushion mesenchyme and Smurf1 -/- mouse embryos show delayed outflow tract septation. SMURF1 is expressed in smooth muscle cells of the coronary arteries and great vessels. Thickness of the aortic smooth muscle cell layer is reduced in Smurf1 -/- mouse embryos. We show that SMURF1 is a negative regulator of cardiomyogenesis and a positive regulator of smooth muscle cell and cardiac fibroblast differentiation, indicating that SMURF1 is important for cell-type specification during heart development. Finally, we provide evidence that SMURF1 localizes at the primary cilium where it may regulate bone morphogenetic protein (BMP) signaling, which controls the initial phase of cardiomyocyte differentiation. In summary, our results demonstrate that SMURF1 is a critical regulator of outflow tract septation and cell-type specification during heart development, and that these effects may in part be mediated via control of cilium-associated BMP signaling.

AB - Smad ubiquitin regulatory factor 1 (SMURF1) is a HECT-type E3 ubiquitin ligase that plays a critical role in vertebrate development by regulating planar cell polarity (PCP) signaling and convergent extension (CE). Here we show that SMURF1 is involved in mammalian heart development. We find that SMURF1 is highly expressed in outflow tract cushion mesenchyme and Smurf1 -/- mouse embryos show delayed outflow tract septation. SMURF1 is expressed in smooth muscle cells of the coronary arteries and great vessels. Thickness of the aortic smooth muscle cell layer is reduced in Smurf1 -/- mouse embryos. We show that SMURF1 is a negative regulator of cardiomyogenesis and a positive regulator of smooth muscle cell and cardiac fibroblast differentiation, indicating that SMURF1 is important for cell-type specification during heart development. Finally, we provide evidence that SMURF1 localizes at the primary cilium where it may regulate bone morphogenetic protein (BMP) signaling, which controls the initial phase of cardiomyocyte differentiation. In summary, our results demonstrate that SMURF1 is a critical regulator of outflow tract septation and cell-type specification during heart development, and that these effects may in part be mediated via control of cilium-associated BMP signaling.

U2 - 10.1038/s41598-018-27854-8

DO - 10.1038/s41598-018-27854-8

M3 - Journal article

C2 - 29934521

AN - SCOPUS:85048944481

SN - 2045-2322

VL - 8

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 9542

ER -

The E3 ubiquitin ligase SMURF1 regulates cell-fate specification and outflow tract septation during mammalian heart development

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