Repression of Sox9 by Jag1 is continuously required to suppress the default chondrogenic fate of vascular smooth muscle cells

Anaïs Briot; Artur Jaroszewicz; Carmen M. Warren; Jing Lu; Marlin Touma; Carsten Rudat; Jennifer J. Hofmann; Rannar Airik; Gerry Weinmaster; Karen Lyons; Yibin Wang; Andreas Kispert; Matteo Pellegrini; M. Luisa Iruela-Arispe

doi:10.1016/j.devcel.2014.11.023

Repression of Sox9 by Jag1 is continuously required to suppress the default chondrogenic fate of vascular smooth muscle cells

Anaïs Briot, Artur Jaroszewicz, Carmen M. Warren, Jing Lu, Marlin Touma, Carsten Rudat, Jennifer J. Hofmann, Rannar Airik, Gerry Weinmaster, Karen Lyons, Yibin Wang, Andreas Kispert, Matteo Pellegrini, M. Luisa Iruela-Arispe^*

^*Corresponding author for this work

Cell & Developmental Biology

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

Abstract

Acquisition and maintenance of vascular smooth muscle fate are essential for the morphogenesis and function of the circulatory system. Loss of contractile properties or changes in the identity of vascular smooth muscle cells (vSMCs) can result in structural alterations associated with aneurysms and vascular wall calcification. Here we report that maturation of sclerotome-derived vSMCs depends on a transcriptional switch between mouse embryonic days 13 and 14.5. At this time, Notch/Jag1-mediated repression of sclerotome transcription factors Pax1, Scx, and Sox9 is necessary tofully enable vSMC maturation. Specifically, Notch signaling in vSMCs antagonizes sclerotome and cartilage transcription factors and promotes upregulation of contractile genes. In the absence of the Notch ligand Jag1, vSMCs acquire a chondrocytic transcriptional repertoire that can lead to ossification. Importantly, our findings suggest that sustained Notch signaling is essential throughout vSMC life to maintain contractile function, prevent vSMC reprogramming, and promote vascular wall integrity.

Original language	English (US)
Pages (from-to)	707-721
Number of pages	15
Journal	Developmental Cell
Volume	31
Issue number	6
DOIs	https://doi.org/10.1016/j.devcel.2014.11.023
State	Published - Dec 22 2014

Funding

The authors wish to thank Michelle Steel, Marianne Ibrahim, and Jun Woo Ha for technical assistance; the contribution of the Tissue Procurement Core Laboratory Shared Resource at UCLA; and Freddy Radke for kindly providing the Jag1lox mouse. This study was supported by funds from the Leducq Foundation (Artemis grant no. FLQ 09CVD02) and the NIH (RO1 HL085618 and 114086 to M.L.I.-A.).

ASJC Scopus subject areas

Molecular Biology
General Biochemistry, Genetics and Molecular Biology
Developmental Biology
Cell Biology

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10.1016/j.devcel.2014.11.023

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Briot, A., Jaroszewicz, A., Warren, C. M., Lu, J., Touma, M., Rudat, C., Hofmann, J. J., Airik, R., Weinmaster, G., Lyons, K., Wang, Y., Kispert, A., Pellegrini, M., & Iruela-Arispe, M. L. (2014). Repression of Sox9 by Jag1 is continuously required to suppress the default chondrogenic fate of vascular smooth muscle cells. Developmental Cell, 31(6), 707-721. https://doi.org/10.1016/j.devcel.2014.11.023

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title = "Repression of Sox9 by Jag1 is continuously required to suppress the default chondrogenic fate of vascular smooth muscle cells",

abstract = "Acquisition and maintenance of vascular smooth muscle fate are essential for the morphogenesis and function of the circulatory system. Loss of contractile properties or changes in the identity of vascular smooth muscle cells (vSMCs) can result in structural alterations associated with aneurysms and vascular wall calcification. Here we report that maturation of sclerotome-derived vSMCs depends on a transcriptional switch between mouse embryonic days 13 and 14.5. At this time, Notch/Jag1-mediated repression of sclerotome transcription factors Pax1, Scx, and Sox9 is necessary tofully enable vSMC maturation. Specifically, Notch signaling in vSMCs antagonizes sclerotome and cartilage transcription factors and promotes upregulation of contractile genes. In the absence of the Notch ligand Jag1, vSMCs acquire a chondrocytic transcriptional repertoire that can lead to ossification. Importantly, our findings suggest that sustained Notch signaling is essential throughout vSMC life to maintain contractile function, prevent vSMC reprogramming, and promote vascular wall integrity.",

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Briot, A, Jaroszewicz, A, Warren, CM, Lu, J, Touma, M, Rudat, C, Hofmann, JJ, Airik, R, Weinmaster, G, Lyons, K, Wang, Y, Kispert, A, Pellegrini, M & Iruela-Arispe, ML 2014, 'Repression of Sox9 by Jag1 is continuously required to suppress the default chondrogenic fate of vascular smooth muscle cells', Developmental Cell, vol. 31, no. 6, pp. 707-721. https://doi.org/10.1016/j.devcel.2014.11.023

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AU - Wang, Yibin

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AU - Pellegrini, Matteo

AU - Iruela-Arispe, M. Luisa

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N2 - Acquisition and maintenance of vascular smooth muscle fate are essential for the morphogenesis and function of the circulatory system. Loss of contractile properties or changes in the identity of vascular smooth muscle cells (vSMCs) can result in structural alterations associated with aneurysms and vascular wall calcification. Here we report that maturation of sclerotome-derived vSMCs depends on a transcriptional switch between mouse embryonic days 13 and 14.5. At this time, Notch/Jag1-mediated repression of sclerotome transcription factors Pax1, Scx, and Sox9 is necessary tofully enable vSMC maturation. Specifically, Notch signaling in vSMCs antagonizes sclerotome and cartilage transcription factors and promotes upregulation of contractile genes. In the absence of the Notch ligand Jag1, vSMCs acquire a chondrocytic transcriptional repertoire that can lead to ossification. Importantly, our findings suggest that sustained Notch signaling is essential throughout vSMC life to maintain contractile function, prevent vSMC reprogramming, and promote vascular wall integrity.

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Repression of Sox9 by Jag1 is continuously required to suppress the default chondrogenic fate of vascular smooth muscle cells

Abstract

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