Myocardin and microRNA-1 modulate bladder activity through connexin 43 expression during post-natal development.
Overactive bladder (OAB) is a pervasive clinical problem involving alterations in both neurogenic and myogenic activity. While there has been some progress in understanding neurogenic inputs to OAB, the mechanisms controlling myogenic bladder activity are unclear. We report the involvement of myocardin (MYOCD) and microRNA-1 (miR-1) in the regulation of connexin 43 (GJA1), a major gap junction in bladder smooth muscle, and the collective role of these molecules during post-natal bladder development. Wild-type (WT) mouse bladders showed normal development from early post-natal to adult including increases in bladder capacity and maintenance of normal sensitivity to cholinergic agents concurrent with down-regulation of MYOCD and several smooth muscle cell (SMC) contractile genes. Myocardin heterozygous-knockout mice exhibited reduced expression of Myocd mRNA and several SMC contractile genes concurrent with bladder SMC hypersensitivity that was mediated by gap junctions. In both cultured rat bladder SMC and in vivo bladders, MYOCD down-regulated GJA1 expression through miR-1 up-regulation. Interestingly, adult myocardin heterozygous-knockout mice showed normal increases in bladder and body weight but lower bladder capacity compared to WT mice. These results suggest that MYOCD down-regulates GJA1 expression via miR-1 up-regulation, thereby contributing to maintenance of normal sensitivity and development of bladder capacity.
Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA. m69ima@kuhp.kyoto-u.ac.jp
Masaaki
M
Imamura
Yoshio
Y
Sugino
Xiaochun
X
Long
Orazio J
OJ
Slivano
Nobuyuki
N
Nishikawa
Naoki
N
Yoshimura
Joseph M
JM
Miano
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D018031:Connexin 43 / Q000235:genetics* / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009119:Muscle Contraction / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D001743:Urinary Bladder / Q000378:metabolism / Q000502:physiology*; D053201:Urinary Bladder, Overactive / Q000378:metabolism / Q000503:physiopathology; D000099251:Myocardin
D018031:Connexin 43; D035683:MicroRNAs; D009687:Nuclear Proteins; D015534:Trans-Activators; D000099251:Myocardin; C543076:GJA1 protein, mouse; C517731:Mirn1 microRNA, mouse