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Heart neurons use clock genes to control myocyte proliferation. Sci Adv 2021 Dec 03;7(49):eabh4181

Date

12/02/2021

Pubmed ID

34851661

Pubmed Central ID

PMC8635446

DOI

10.1126/sciadv.abh4181

Scopus ID

2-s2.0-85120689228 (requires institutional sign-in at Scopus site)   16 Citations

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 regen5eration.

Author List

Tampakakis E, Gangrade H, Glavaris S, Htet M, Murphy S, Lin BL, Liu T, Saberi A, Miyamoto M, Kowalski W, Mukouyama YS, Lee G, Minichiello L, Kwon C

Author

Brian L. Lin PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin