Mesodermal expression of Moz is necessary for cardiac septum development.
Ventricular septal defects (VSDs) are the most commonly occurring congenital heart defect. They are regularly associated with complex syndromes, including DiGeorge syndrome and Holt-Oram syndrome, which are characterised by haploinsufficiency for the T-box transcription factors TBX1 and TBX5, respectively. The histone acetyltransferase monocytic leukaemia zinc finger protein, MOZ (MYST3/KAT6A), is required for the expression of the Tbx1 and Tbx5 genes. Homozygous loss of MOZ results in DiGeorge syndrome-like defects including VSD. The Moz gene is expressed in the ectodermal, mesodermal and endodermal aspects of the developing pharyngeal apparatus and heart; however it is unclear in which of these tissues MOZ is required for heart development. The role of MOZ in the activation of Tbx1 would suggest a requirement for MOZ in the mesoderm, because deletion of Tbx1 in the mesoderm causes VSDs. Here, we investigated the tissue-specific requirements for MOZ in the mesoderm. We demonstrate that Mesp1-cre-mediated deletion of Moz results in high penetrance of VSDs and overriding aorta and a significant decrease in MOZ-dependant Tbx1 and Tbx5 expression. Together, our data suggest that the molecular pathogenesis of VSDs in Moz germline mutant mice is due to loss of MOZ-dependant activation of mesodermal Tbx1 and Tbx5 expression.
Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Melbourne 3052, Victoria, Australia.
Hannah K
HK
Vanyai
Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Melbourne 3052, Victoria, Australia. Electronic address: tthomas@wehi.edu.au.
Tim
T
Thomas
Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Melbourne 3052, Victoria, Australia. Electronic address: avoss@wehi.edu.au.
Anne K
AK
Voss
D000818:Animals; D004062:DiGeorge Syndrome / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology; D006345:Heart Septal Defects, Ventricular / Q000235:genetics*; D006346:Heart Septum / Q000166:cytology / Q000196:embryology*; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D038081:Organogenesis / Q000235:genetics; D020825:T-Box Domain Proteins / Q000235:genetics*
D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; C491573:Tbx1 protein, mouse; D051548:Histone Acetyltransferases; C511438:MOZ protein, mouse
Cardiac septal defect; KAT6A; MOZ; MYST3; Tbx1; Tbx5