title: Activation dynamics and signaling properties of Notch3 receptor in the developing pulmonary artery.
abstract: Notch3 signaling is fundamental for arterial specification of systemic vascular smooth muscle cells (VSMCs). However, the developmental role and signaling properties of the Notch3 receptor in the mouse pulmonary artery remain unknown. Here, we demonstrate that Notch3 is expressed selectively in pulmonary artery VSMCs, is activated from late fetal to early postnatal life, and is required to maintain the morphological characteristics and smooth muscle gene expression profile of the pulmonary artery after birth. Using a conditional knock-out mouse model, we show that Notch3 receptor activation in VSMCs is Jagged1-dependent. In vitro VSMC lentivirus-mediated Jagged1 knockdown, confocal localization analysis, and co-culture experiments revealed that Notch3 activation is cell-autonomous and occurs through the physical engagement of Notch3 and VSMC-derived Jagged1 in the interior of the same cell. Although the current models of mammalian Notch signaling involve a two-cell system composed of a signal-receiving cell that expresses a Notch receptor on its surface and a neighboring signal-sending cell that provides membrane-bound activating ligand, our data suggest that pulmonary artery VSMC Notch3 activation is cell-autonomous. This unique mechanism of Notch activation may play an important role in the maturation of the pulmonary artery during the transition to air breathing.
authors.affiliation: Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Shamik
authors.initials: S
authors.lastname: Ghosh
authors.forename: Jesus R
authors.initials: JR
authors.lastname: Paez-Cortez
authors.forename: Karthik
authors.initials: K
authors.lastname: Boppidi
authors.forename: Michelle
authors.initials: M
authors.lastname: Vasconcelos
authors.forename: Monideepa
authors.initials: M
authors.lastname: Roy
authors.forename: Wellington
authors.initials: W
authors.lastname: Cardoso
authors.forename: Xingbin
authors.initials: X
authors.lastname: Ai
authors.forename: Alan
authors.initials: A
authors.lastname: Fine
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D000072100:Jagged-1 Protein; D008168:Lung / Q000098:blood supply* / Q000254:growth & development*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D009928:Organ Specificity; D011247:Pregnancy; D021381:Protein Transport; D011651:Pulmonary Artery / Q000166:cytology* / Q000378:metabolism*; D051381:Rats; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D015415:Biomarkers; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C000606275:Jag1 protein, rat; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins