title: Time-dependent regulation of neuregulin-1β/ErbB/ERK pathways in cardiac differentiation of mouse embryonic stem cells.
abstract: Neuregulin-1β (NRG-1β)/ErbB signaling plays crucial roles in the cardiac differentiation of mouse embryonic stem cells (ESCs), but its roles and the underlying mechanisms in cardiac differentiation are incompletely understood. This study showed that NRG-1β significantly increased the percentage of beating embryoid bodies (EBs) and up-regulated the gene expressions of Nkx2.5, GATA4, α-actin, MLC-2v, and ANF in a time-dependent manner, with no effect on the gene expressions of HCN4 and Tbx3. Inhibition of ErbB receptors with AG1478 significantly decreased the percentage of beating EBs; down-regulated the gene expressions of Nkx2.5, GATA4, MLC-2v, ANF, and α-actin; and concomitantly up-regulated the gene expressions of HCN4 and Tbx3 in a time-dependent manner. Moreover, the up-regulation of transcripts for Nkx2.5 and GATA4 by NRG-1β was blocked by the extracellular signal-related kinases (ERK) 1/2 inhibitor, U0126. However, U0126 could not inhibit the transcript up-regulations of MLC-2v and ANF by NRG-1β. The protein quantitation results were consistent with those of gene quantitation. Our results suggest that NRG-1β/ErbB signaling plays critical roles in the cardiac differentiation of mouse ESCs and in the subtype specification of cardiomyocytes in a time-dependent manner. The ERK1/2 pathway may be involved in the early cardiogenesis, but not in the subtype specification of cardiomyocytes.
authors.affiliation: Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, China. dr_chenming@163.com
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Bi
authors.forename: Zhi-Quan
authors.initials: ZQ
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.forename: Xue-Dong
authors.initials: XD
authors.lastname: Gan
authors.forename: Yang-Gan
authors.initials: YG
authors.lastname: Wang
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D002070:Butadienes / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D058732:Embryoid Bodies / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050991:GATA4 Transcription Factor / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D018994:Myosin Light Chains / Q000235:genetics; D020890:Neuregulin-1 / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D020825:T-Box Domain Proteins / Q000235:genetics; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000199:Actins; D002070:Butadienes; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; C578706:Hcn4 protein, mouse; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; C521958:Mylpf protein, mouse; D018994:Myosin Light Chains; D020890:Neuregulin-1; D009570:Nitriles; C484469:Nkx2-5 protein, mouse; D011799:Quinazolines; D020825:T-Box Domain Proteins; C491460:Tbx3 protein, mouse; D014157:Transcription Factors; D020032:Tyrphostins; C113580:U 0126; C101044:RTKI cpd; D009320:Atrial Natriuretic Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases