title: CREG1 Interacts with Sec8 to Promote Cardiomyogenic Differentiation and Cell-Cell Adhesion.
abstract: Understanding the regulation of cell-cell interactions during the formation of compact myocardial structures is important for achieving true cardiac regeneration through enhancing the integration of stem cell-derived cardiomyocytes into the recipient myocardium. In this study, we found that cellular repressor of E1A-stimulated genes 1 (CREG1) is highly expressed in both embryonic and adult hearts. Gain- and loss-of-function analyses demonstrated that CREG1 is required for differentiation of mouse embryonic stem (ES) cell into cardiomyocytes and the formation of cohesive myocardium-like structures in a cell-autonomous fashion. Furthermore, CREG1 directly interacts with Sec8 of the exocyst complex, which tethers vesicles to the plasma membrane. Site-directed mutagenesis and rescue of CREG1 knockout ES cells showed that CREG1 binding to Sec8 is required for cardiomyocyte differentiation and cohesion. Mechanistically, CREG1, Sec8, and N-cadherin colocalize at intercalated discs in vivo and are enriched at cell-cell junctions in cultured cardiomyocytes. CREG1 overexpression enhances the assembly of adherens and gap junctions. By contrast, its knockout inhibits the Sec8-N-cadherin interaction and induces their degradation. These results suggest that the CREG1 binding to Sec8 enhances the assembly of intercellular junctions and promotes cardiomyogenesis. Stem Cells 2016;34:2648-2660.
authors.affiliation: Department of Surgery, Robert Wood Johnson Medical School.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Surgery, Robert Wood Johnson Medical School.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Surgery, Robert Wood Johnson Medical School.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers-the State University of New Jersey, USA.
authors.forename: Shu-Chan
authors.initials: SC
authors.lastname: Hsu
authors.affiliation: Department of Surgery, Robert Wood Johnson Medical School.
authors.forename: Siavash
authors.initials: S
authors.lastname: Saadat
authors.affiliation: Department of Surgery, Robert Wood Johnson Medical School.
authors.forename: June
authors.initials: J
authors.lastname: Hsu
authors.affiliation: Department of Surgery, Robert Wood Johnson Medical School.
authors.forename: Saum A
authors.initials: SA
authors.lastname: Rahimi
authors.affiliation: Department of Surgery, Robert Wood Johnson Medical School.
authors.forename: Leonard Y
authors.initials: LY
authors.lastname: Lee
authors.affiliation: Department of Cardiology, The General Hospital of Shenyang Military Region, Shenyang, Liaoning, China.
authors.forename: Chenghui
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Cardiology, The General Hospital of Shenyang Military Region, Shenyang, Liaoning, China.
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Cardiology, The General Hospital of Shenyang Military Region, Shenyang, Liaoning, China.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Han
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion; D002450:Cell Communication; D002454:Cell Differentiation; D058732:Embryoid Bodies / Q000166:cytology / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism / Q000648:ultrastructure; D018507:Gene Expression Regulation, Developmental; D005816:Genetic Complementation Test; D006321:Heart / Q000254:growth & development*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D038081:Organogenesis / Q000235:genetics*; D061251:Primary Cell Culture; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D015820:Cadherins; D002352:Carrier Proteins; C489083:Cdh2 protein, mouse; C485248:Creg protein, mouse; D008565:Membrane Proteins; D012097:Repressor Proteins; C489608:Sec8l1 protein, mouse
keywords: Cardiac differentiation; Embryonic stem cells; Exocyst; Intercalated discs