Micro‐RNA‐205 Regulates Heart Size Through Direct Modulation of the Hippo Pathway

Abstract

During fetal development, the mammalian myocardium undergoes a period of hyperplastic growth, which establishes the number of cardiomyocytes in the adult heart. After birth, cardiomyocytes proceed through a final round of cell division in the absence cytokinesis that results in binucleation of >95% of adult cardiomyocytes. Nearly all subsequent increase in myocardial mass is due to myocardial hypertrophy, with extremely low number of new cardiomyocytes being produced throughout post‐natal life. Despite the importance of this phenomenon, little is known about the molecular/genetic basis, especially with regard to the role of micro‐RNAs, for the transition from hyperplastic to hypertrophic‐based myocardial growth.We hypothesize a specific perinatal heart micro‐RNA‐mediated gene program is necessary for the normal transition from a fetal heart to an adult heart gene program.To identify the molecular mechanisms and genetic pathways involved in cardiac myocyte differentiation, RNA was isolated from E19, and 1, 3, 5, 7, 10 and 35‐day old mouse hearts (n=9 hearts/time point pooled). Cardiomyocyte micro‐RNA profiles (n=3 arrays/time point) were measured and bioinformatic analysis was used to identify genes that are transiently and significantly changing (p<0.05, fold change >1.5) during the perinatal period.Our analysis identified microRNA‐205 as a candidate for playing a role in the cardiac transitional program. Previous studies have shown a global knockout of miR‐205 to be neonatally lethal. We observe a transient 20‐fold increase in miR‐205 expression between day 1 and day 5 of post‐natal life, with levels returning to baseline by day 10. In‐situ hybridization revealed miR‐205 expression to be restricted to the epicardium of the heart.Mice harbouring a cardiomyocyte‐specific deletion of miR‐205 using αMHC‐Cre are born healthy with expected Mendelian ratios, and develop through the neonatal period normally. Hearts collected from adult mice show signs of abnormal growth and hypertrophy, up to 50% larger than controls. Previous studies demonstrated that miR‐205 directly targets YAP within the evolutionarily conserved hippo pathway that controls organ size. Hearts lacking miR‐205 exhibit a substantial increase in YAP protein expression. Increased cardiac size has been demonstrated in a constitutively active YAP transgenic mouse model. We conclude that miR‐205 plays a direct role in regulating post‐natal heart size through direct modulation of the Hippo pathway.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.