Projects per year
Abstract
Mutations in the Nkx2-5 gene are a main cause of congenital heart disease. Several studies have addressed the phenotypic consequences of disrupting the Nkx2-5 gene locus, although animal models to date failed to recapitulate the full spectrum of the human disease. Here, we describe a new Nkx2-5 point mutation murine model, akin to its human counterpart disease-generating mutation. Our model fully reproduces the morphological and physiological clinical presentations of the disease and reveals an understudied aspect of Nkx2-5-driven pathology, a primary right ventricular dysfunction. We further describe the molecular consequences of disrupting the transcriptional network regulated by Nkx2-5 in the heart and show that Nkx2-5-dependent perturbation of the Wnt signaling pathway promotes heart dysfunction through alteration of cardiomyocyte metabolism. Our data provide mechanistic insights on how Nkx2-5 regulates heart function and metabolism, a link in the study of congenital heart disease, and confirms that our models are the first murine genetic models to our knowledge to present all spectra of clinically relevant adult congenital heart disease phenotypes generated by NKX2-5 mutations in patients.
Original language | English |
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Article number | e88271 |
Pages (from-to) | e88271 |
Number of pages | 18 |
Journal | JCI Insight |
Volume | 2 |
Issue number | 6 |
DOIs | |
Publication status | Published - 23 Mar 2017 |
Projects
- 2 Finished
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Using Nkx2-5 knock-in mouse models to understand complex cardiac diseases
Ramialison, M., Da Costa, M. & Rosenthal, N.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/14 → 31/12/16
Project: Research
Equipment
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Biomedical Imaging (MBI)
Kylie Reid (Manager), Robert Brkljaca (Manager), Christoph Hagemeyer (Other) & David Wright (Other)
Office of the Vice-Provost (Research and Research Infrastructure)Facility/equipment: Facility
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Genome Modification Platform
Jeanette Rientjes (Manager)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility
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Monash Micro Imaging
Stephen Firth (Manager), Alex Fulcher (Operator), Oleks Chernyavskiy (Operator), Margaret Rzeszutek (Other), David Potter (Manager), Volker Hilsenstein (Operator), Juan Nunez-Iglesias (Other), Stephen Cody (Manager), Irena Carmichael (Operator), Betty Kouskousis (Other), Sarah Creed (Manager) & Giulia Ballerin (Operator)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility