期刊
DEVELOPMENTAL BIOLOGY
卷 470, 期 -, 页码 95-107出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ydbio.2020.11.008
关键词
Zebrafish; Second heart field; mef2c; Cardiomyocyte; Growth
资金
- PhD programme of the British Heart Foundation Centre of Research Excellence at King's College London
- MRC [G1001029, MR/N021231/1]
- British Heart Foundation [PG/14/12/30664]
- MRC [G1001029, G0300213, MR/N021231/1] Funding Source: UKRI
During heart formation, significant growth and morphogenesis occur, with cell proliferation, cardiomyocyte addition, and hypertrophy playing key roles in ventricle growth. Loss of Mef2c activity affects cardiomyocyte addition and differentiation, leading to a smaller ventricle at early stages but recovery in later development.
During heart formation, the heart grows and undergoes dramatic morphogenesis to achieve efficient embryonic function. Both in fish and amniotes, much of the growth occurring after initial heart tube formation arises from second heart field (SHF)-derived progenitor cell addition to the arterial pole, allowing chamber formation. In zebrafish, this process has been extensively studied during embryonic life, but it is unclear how larval cardiac growth occurs beyond 3 days post-fertilisation (dpf). By quantifying zebrafish myocardial growth using live imaging of GFP-labelled myocardium we show that the heart grows extensively between 3 and 5 dpf. Using methods to assess cell division, cellular development timing assay and Kaede photoconversion, we demonstrate that proliferation, CM addition, and hypertrophy contribute to ventricle growth. Mechanistically, we show that reduction in Mef2c activity (mef2ca(+/-);mef2cb(-/-)), downstream or in parallel with Nkx2.5 and upstream of Ltbp3, prevents some CM addition and differentiation, resulting in a significantly smaller ventricle by 3 dpf. After 3 dpf, however, CM addition in mef2ca(+/-);mef2cb(-/-) mutants recovers to a normal pace, and the heart size gap between mutants and their siblings diminishes into adulthood. Thus, as in mice, there is an early time window when SHF contribution to the myocardium is particularly sensitive to loss of Mef2c activity.
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