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

Dev Cell. 2014 Dec 22;31(6):707-21. doi: 10.1016/j.devcel.2014.11.023.

Authors

Affiliations

¹ Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Division of Anesthesiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Institut fur Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
⁴ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: arispe@mcdb.ucla.edu.

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 to fully 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Active Transport, Cell Nucleus
Animals
Calcium-Binding Proteins / metabolism*
Cartilage / metabolism
Cell Lineage
Chondrocytes / cytology
Chondrogenesis / physiology*
Female
Gene Expression Regulation, Developmental*
Intercellular Signaling Peptides and Proteins / metabolism*
Jagged-1 Protein
Ligands
Male
Membrane Proteins / metabolism*
Mice
Muscle Contraction
Muscle, Smooth, Vascular / cytology*
Myocytes, Smooth Muscle / cytology*
Receptors, Notch / metabolism
SOX9 Transcription Factor / metabolism*
Sequence Analysis, RNA
Serrate-Jagged Proteins
Signal Transduction
Time Factors
Transcription Factors / metabolism

Substances

Calcium-Binding Proteins
Intercellular Signaling Peptides and Proteins
Jag1 protein, mouse
Jagged-1 Protein
Ligands
Membrane Proteins
Receptors, Notch
SOX9 Transcription Factor
Serrate-Jagged Proteins
Sox9 protein, mouse
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding