title: Tbx5 and Osr1 interact to regulate posterior second heart field cell cycle progression for cardiac septation.
abstract: BACKGROUND
  Mutations of TBX5 cause Holt-Oram syndrome (HOS) in humans, a disease characterized by atrial or occasionally ventricular septal defects in the heart and skeletal abnormalities of the upper extremity. Previous studies have demonstrated that Tbx5 regulates Osr1 expression in the second heart field (SHF) of E9.5 mouse embryos. However, it is unknown whether and how Tbx5 and Osr1 interact in atrial septation.
  
  
  OBJECTIVE
  To determine if and how Tbx5 and Osr1 interact in the posterior SHF for cardiac septation.
  
  
  RESULTS
  In the present study, genetic inducible fate mapping showed that Osr1-expressing cells contribute to atrial septum progenitors between E8.0 and E11.0. Osr1 expression in the pSHF was dependent on the level of Tbx5 at E8.5 and E9.5 but not E10.5, suggesting that the embryo stage before E10.5 is critical for Tbx5 interacting with Osr1 in atrial septation. Significantly more atrioventricular septal defects (AVSDs) were observed in embryos with compound haploinsufficiency for Tbx5 and Osr1. Conditional compound haploinsufficiency for Tbx5 and Osr1 resulted in a significant cell proliferation defect in the SHF, which was associated with fewer cells in the G2 and M phases and a decreased level of Cdk6 expression. Remarkably, genetically targeted disruption of Pten expression in atrial septum progenitors rescued AVSDs caused by Tbx5 and Osr1 compound haploinsufficiency. There was a significant decrease in Smo expression, which is a Hedgehog (Hh) signaling pathway modulator, in the pSHF of Osr1 knockout embryos at E9.5, implying a role for Osr1 in regulating Hh signaling.
  
  
  CONCLUSIONS
  Tbx5 and Osr1 interact to regulate posterior SHF cell cycle progression for cardiac septation.
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; Department of Gerontology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Lun
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA.
authors.forename: Jielin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Olson
authors.affiliation: Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Wynne
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA. Electronic address: linglin.xie@med.und.edu.
authors.forename: Linglin
authors.initials: L
authors.lastname: Xie
mesh_terms: D000818:Animals; D054087:Atrial Septum / Q000196:embryology*; D002453:Cell Cycle; D053595:Embryonic Stem Cells / Q000378:metabolism; D004843:Epistasis, Genetic; D057809:HEK293 Cells; D006801:Humans; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C121641:Osr1 protein, mouse; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D014157:Transcription Factors; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Atrioventricular septal defects (AVSDs); Cell cycle; Osr1; Pten; Second heart field; Tbx5