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 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.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Briot
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Artur
authors.initials: A
authors.lastname: Jaroszewicz
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Warren
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: Division of Anesthesiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Marlin
authors.initials: M
authors.lastname: Touma
authors.affiliation: Institut fur Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Rudat
authors.affiliation: Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Hofmann
authors.affiliation: Institut fur Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
authors.forename: Rannar
authors.initials: R
authors.lastname: Airik
authors.affiliation: 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.
authors.forename: Gerry
authors.initials: G
authors.lastname: Weinmaster
authors.affiliation: 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.
authors.forename: Karen
authors.initials: K
authors.lastname: Lyons
authors.affiliation: Division of Anesthesiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institut fur Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
authors.affiliation: 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.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: 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.
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Iruela-Arispe
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002356:Cartilage / Q000378:metabolism; D019070:Cell Lineage; D019902:Chondrocytes / Q000166:cytology; D020219:Chondrogenesis / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D051880:Receptors, Notch / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D055758:SOX9 Transcription Factor; D000072099:Serrate-Jagged Proteins; C527933:Sox9 protein, mouse; D014157:Transcription Factors