Heart neurons use clock genes to control myocyte proliferation

ARTICLE: Heart neurons use clock genes to control myocyte proliferation

AUTHORS: Emmanouil TampakakisHarshi Gangrade, Stephanie Glavaris, Myo HtetSean MurphyBrian Leei LinTing LiuAmir SaberiMatthew Miyamoto, William Kowalski, Yoh-Suke Mukouyama, Gabsang Lee, Liliana Minichiello, Chulan Kwon

JOURNAL: Sci Adv. 2021 Dec 3;7(49):eabh4181. doi: 10.1126/sciadv.abh4181. Epub 2021 Dec 1.

Abstract

Neurons can regulate the development, pathogenesis, and regeneration of target organs. However, the role of neurons during heart development and regeneration remains unclear. We genetically inhibited sympathetic innervation in vivo, which resulted in heart enlargement with an increase in cardiomyocyte number. Transcriptomic and protein analysis showed down-regulation of the two clock gene homologs Period1/Period2 (Per1/Per2) accompanied by up-regulation of cell cycle genes. Per1/Per2 deletion increased heart size and cardiomyocyte proliferation, recapitulating sympathetic neuron–deficient hearts. Conversely, increasing sympathetic activity by norepinephrine treatment induced Per1/Per2 and suppressed cardiomyocyte proliferation. We further found that the two clock genes negatively regulate myocyte mitosis entry through the Wee1 kinase pathway. Our findings demonstrate a previously unknown link between cardiac neurons and clock genes in regulation of cardiomyocyte proliferation and heart size and provide mechanistic insights for developing neuromodulation strategies for cardiac regeneration.

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