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NPJ Regen Med 2021 Jun 29;61:36. doi: 10.1038/s41536-021-00146-y.
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Fosl1 is vital to heart regeneration upon apex resection in adult Xenopus tropicalis.

Wu HY , Zhou YM , Liao ZQ , Zhong JW , Liu YB , Zhao H , Liang CQ , Huang RJ , Park KS , Feng SS , Zheng L , Cai DQ , Qi XF .

Cardiovascular disease is the leading cause of death in the world due to losing regenerative capacity in the adult heart. Frogs possess remarkable capacities to regenerate multiple organs, including spinal cord, tail, and limb, but the response to heart injury and the underlying molecular mechanism remains largely unclear. Here we demonstrated that cardiomyocyte proliferation greatly contributes to heart regeneration in adult X. tropicalis upon apex resection. Using RNA-seq and qPCR, we found that the expression of Fos-like antigen 1 (Fosl1) was dramatically upregulated in early stage of heart injury. To study Fosl1 function in heart regeneration, its expression was modulated in vitro and in vivo. Overexpression of X. tropicalis Fosl1 significantly promoted the proliferation of cardiomyocyte cell line H9c2. Consistently, endogenous Fosl1 knockdown suppressed the proliferation of H9c2 cells and primary cardiomyocytes isolated from neonatal mice. Taking use of a cardiomyocyte-specific dominant-negative approach, we show that blocking Fosl1 function leads to defects in cardiomyocyte proliferation during X. tropicalis heart regeneration. We further show that knockdown of Fosl1 can suppress the capacity of heart regeneration in neonatal mice, but overexpression of Fosl1 can improve the cardiac function in adult mouse upon myocardium infarction. Co-immunoprecipitation, luciferase reporter, and ChIP analysis reveal that Fosl1 interacts with JunB and promotes the expression of Cyclin-T1 (Ccnt1) during heart regeneration. In conclusion, we demonstrated that Fosl1 plays an essential role in cardiomyocyte proliferation and heart regeneration in vertebrates, at least in part, through interaction with JunB, thereby promoting expression of cell cycle regulators including Ccnt1.

PubMed ID: 34188056
PMC ID: PMC8242016
Article link: NPJ Regen Med
Grant support: [+]

Species referenced: Xenopus tropicalis Xenopus laevis
Genes referenced: actn1 anapc11 ccna1 ccna2 ccnc ccnd1 ccnd2 ccne2 ccng2 ccnk ccnl1 ccnl2 ccno ccnt1 ccnt2 ccny cdk1 cdk12 cdk13 cdk14 cdk17 cdk2 cdk4 cdk6 cdk8 cdk9 cdkn1a cdkn2b cdkn2c cdkn2d cdknx chek1 chek2 dact1 fas fos fosl1 junb jund myc rcc2 rgcc sgk1 sik1 tnni3
GO keywords: cardiac muscle tissue regeneration [+]
Antibodies: mki67 Ab1

Disease Ontology terms: cardiovascular system disease
Phenotypes: Xtr Wt + heart injury (Fig 1d) [+]

Article Images: [+] show captions
References [+] :
Arrell, Cardiopoietic stem cell therapy restores infarction-altered cardiac proteome. 2020, Pubmed