Identification and regulation of a novel leptin receptor-linked enhancer during zebrafish ventricle regeneration

Aims: Vertebrates vary greatly in their abilities to regenerate injured hearts. Zebrafish possess a remarkable capacity for cardiac regeneration, making them an excellent model for regeneration research. Recent studies have reported the activation and underlying regulatory mechanisms of Leptin b (lepb) and the Leptin b-linked enhancer (LEN) in injured hearts. However, the regenerative response activity of the Leptin receptor (lepr) and its regulatory mechanisms still warrant further exploration.

Materials and methods: We identified a novel lepr-linked enhancer (leprEnh) and generated a stable transgenic zebrafish line for validation. We also employed a genetic ventricle ablation system to elucidate the mechanisms governing its activation. Immunofluorescence, in situ hybridization and confocal imaging of larvae treated with various inhibitors during ventricle regeneration were performed.

Key findings: Our results revealed that both lepr expression and leprEnh-directed EGFP fluorescence were weakly expressed in the ventricle during early heart development but displayed a sharp increase after ventricle ablation. Strong injury response activity was also observed in the atrium. Furthermore, the regeneration-responsive activity was attenuated by hemodynamic force alteration and was modulated by Notch, ErbB2 and BMP signaling pathways.

Significance: Our study sheds light on the regulation of lepr and leprEnh during heart regeneration and provide a basis for screening for novel therapeutic targets for myocardial infarction.

Heart regeneration; Hemodynamics; lepr; lepr-linked enhancer.