title: Neuregulin-1β induces embryonic stem cell cardiomyogenesis via ErbB3/ErbB2 receptors.
abstract: NRG-1β (neuregulin-1β) serves multiple functions during embryonic heart development by signalling through ErbB family receptor tyrosine kinases (ErbB2, ErbB3 and ErbB4). Previous studies reported that NRG-1β induces cardiomyogenesis of mESCs (mouse embryonic stem cells) at the later stages of differen-tiation through ErbB4 receptor activation. In the present study we systematically examined NRG-1β induction of cardiac myocytes in mESCs and identified a novel time window, the first 48 h, for NRG-1β-based cardiomyogenesis. At this time point ErbB3, but not ErbB4, is expressed. In contrast with the later differentiation of mESCs in which NRG-1β induces cardiomyogenesis via the ErbB4 receptor, we found that knocking down ErbB3 or ErbB2 with siRNA during the early differentiation inhibited NRG-1β-induced cardiomyogenesis in mESCs. Microarray analysis of RNA expression at this early time point indicated that NRG-1β treatment in mESCs resulted in gene expression changes important to differentiation including up-regulation of components of PI3K (phosphoinositide 3-kinase), a known mediator of the NRG-1β/ErbB signalling pathway, as well as activation of CREB (cAMP-response-element-binding protein). Further study demonstrated that the NRG-1β-induced phosphorylation of CREB was required for cardiomyogenesis of mESCs. In summary, we report a previously unrecognized role for NRG-1β/ErbB3/CREB signalling at the pre-mesoderm stage for stem cell cardiac differentiation.
authors.forename: Jijun
authors.initials: J
authors.lastname: Hao
authors.affiliation: †Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, U.S.A.
authors.forename: Cristi L
authors.initials: CL
authors.lastname: Galindo
authors.affiliation: †Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, U.S.A.
authors.forename: Truc-Linh
authors.initials: TL
authors.lastname: Tran
authors.affiliation: †Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, U.S.A.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Sawyer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D053595:Embryonic Stem Cells / Q000502:physiology*; D055785:Gene Knockdown Techniques; D051379:Mice; D032383:Myocytes, Cardiac / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology; D020890:Neuregulin-1 / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency* / Q000502:physiology*; D020893:Receptor, ErbB-3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C492004:Creb1 protein, mouse; C117467:neuregulin beta; C581292:ERBB3 protein, human; C524056:Erbb2 protein, mouse