While the mammalian heart could regenerate during the neonatal stage, such an endogenous regenerative capacity is lost with age. Importantly, replication of cardiomyocytes is found to be the key mechanism responsible for neonatal cardiac regeneration. Unraveling the transcriptional regulatory network for inducing cardiomyocyte replication will, therefore, provide important insights into development of novel therapies to drive cardiac repair after injury. Here, we explored if the key cardiac transcription factor GATA4 is required for neonatal mouse heart regeneration. Using the neonatal mouse heart cryoinjury and apical resection models with an inducible loss of GATA4 specifically in cardiomyocytes, we found severely depressed ventricular function in the Gata4 ablated mice (mutant) after injury. This was accompanied with reduced cardiomyocyte replication. In addition, the mutant hearts displayed impaired coronary angiogenesis and increased hypertrophy and fibrosis after injury. Mechanistically, we found that the paracrine factor FGF16 was significantly reduced in the mutant hearts after injury compared with that of the littermate controls and was directly regulated by GATA4. Cardiac specific overexpression of FGF16 via adeno-associated virus subtype 9 (AAV9) in the mutant hearts partially rescued the cryoinjury-induced cardiac hypertrophy; promoted cardiomyocyte replication and improved heart function after injury. Altogether, our data demonstrated that GATA4 is required for neonatal heart regeneration through regulation of Fgf16, suggesting that paracrine factors could be of potential use in promoting myocardial repair.
GATA4 regulates Fgf16 to promote heart repair after injury
Currently Viewing Accepted Manuscript - Newer Version Available
Wei Yu, Xiuzhen Huang, Xueying Tian, Hui Zhang, Lingjuan He, Yue Wang, Yu Nie, Shengshou Hu, Zhiqiang Lin, Bin Zhou, William Pu, Kathy O. Lui, Bin Zhou; GATA4 regulates Fgf16 to promote heart repair after injury. Development 2016; dev.130971. doi: https://doi.org/10.1242/dev.130971
Download citation file:
Advertisement
Call for papers: Uncovering Developmental Diversity
Development invites you to submit your latest research to our upcoming special issue: Uncovering Developmental Diversity. This issue will be coordinated by our academic Editor Cassandra Extavour (Harvard University, USA) alongside two Guest Editors: Liam Dolan (Gregor Mendel Institute of Molecular Plant Biology, Austria) and Karen Sears (University of California Los Angeles, USA).
Choose Development in 2024
In this Editorial, Development Editor-in-Chief James Briscoe and Executive Editor Katherine Brown explain how you support your community by publishing in Development and how the journal champions serious science, community connections and progressive publishing.
Journal Meeting: From Stem Cells to Human Development
Register now for the 2024 Development Journal Meeting From Stem Cells to Human Development. Early-bird registration deadline: 3 May. Abstract submission deadline: 21 June.
Pluripotency of a founding field: rebranding developmental biology
This collaborative Perspective, the result of a workshop held in 2023, proposes a set of community actions to increase the visibility of the developmental biology field. The authors make recommendations for new funding streams, frameworks for collaborations and mechanisms by which members of the community can promote themselves and their research.
Read & Publish Open Access publishing: what authors say
We have had great feedback from authors who have benefitted from our Read & Publish agreement with their institution and have been able to publish Open Access with us without paying an APC. Read what they had to say.