title: Notch initiates the endothelial-to-mesenchymal transition in the atrioventricular canal through autocrine activation of soluble guanylyl cyclase.
abstract: The heart is the most common site of congenital defects, and valvuloseptal defects are the most common of the cardiac anomalies seen in the newborn. The process of endothelial-to-mesenchymal transition (EndMT) in the cardiac cushions is a required step during early valve development, and Notch signaling is required for this process. Here we show that Notch activation induces the transcription of both subunits of the soluble guanylyl cyclase (sGC) heterodimer, GUCY1A3 and GUCY1B3, which form the nitric oxide receptor. In parallel, Notch also promotes nitric oxide (NO) production by inducing Activin A, thereby activating a PI3-kinase/Akt pathway to phosphorylate eNOS. We thus show that the activation of sGC by NO through a Notch-dependent autocrine loop is necessary to drive early EndMT in the developing atrioventricular canal (AVC).
authors.affiliation: Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver BC V5Z 1L3, Canada.
authors.forename: Alex C Y
authors.initials: AC
authors.lastname: Chang
authors.forename: YangXin
authors.initials: Y
authors.lastname: Fu
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Garside
authors.forename: Kyle
authors.initials: K
authors.lastname: Niessen
authors.forename: Linda
authors.initials: L
authors.lastname: Chang
authors.forename: Megan
authors.initials: M
authors.lastname: Fuller
authors.forename: Audi
authors.initials: A
authors.lastname: Setiadi
authors.forename: Justin
authors.initials: J
authors.lastname: Smrz
authors.forename: Alastair
authors.initials: A
authors.lastname: Kyle
authors.forename: Andrew
authors.initials: A
authors.lastname: Minchinton
authors.forename: Marco
authors.initials: M
authors.lastname: Marra
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Hoodless
authors.forename: Aly
authors.initials: A
authors.lastname: Karsan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation / Q000379:methods; D054089:Endocardial Cushions / Q000166:cytology*; D004727:Endothelium / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006162:Guanylate Cyclase / Q000378:metabolism*; D008297:Male; D008648:Mesoderm / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D034622:RNA Interference / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase
chemical_list: C000605668:Gucy1a3 protein, mouse; C000605673:Gucy1b3 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D051880:Receptors, Notch; D052250:Nitric Oxide Synthase Type III; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase