The miR-143-adducin3 pathway is essential for cardiac chamber morphogenesis.
Discovering the genetic and cellular mechanisms that drive cardiac morphogenesis remains a fundamental goal, as three-dimensional architecture greatly impacts functional capacity. During development, accurately contoured chambers balloon from a primitive tube in a process characterized by regional changes in myocardial cell size and shape. How these localized changes are achieved remains elusive. Here, we show in zebrafish that microRNA-143 (miR-143) is required for chamber morphogenesis through direct repression of adducin3 (add3), which encodes an F-actin capping protein. Knockdown of miR-143 or disruption of the miR-143-add3 interaction inhibits ventricular cardiomyocyte F-actin remodeling, which blocks their normal growth and elongation and leads to ventricular collapse and decreased contractility. Using mosaic analyses, we find that miR-143 and add3 act cell-autonomously to control F-actin dynamics and cell morphology. As proper chamber emergence relies on precise control of cytoskeletal polymerization, Add3 represents an attractive target to be fine-tuned by both uniform signals, such as miR-143, and undiscovered localized signals. Together, our data uncover the miR-143-add3 genetic pathway as essential for cardiac chamber formation and function through active adjustment of myocardial cell morphology.
Deacon
Dekker C
DC
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Nevis
Kathleen R
KR
Cashman
Timothy J
TJ
Zhou
Yong
Y
Zhao
Long
L
Washko
Daniel
D
Guner-Ataman
Burcu
B
Burns
C Geoffrey
CG
Burns
Caroline E
CE
D020413:3' Untranslated Regions; D000199:Actins / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002148:Calmodulin-Binding Proteins / Q000235:genetics* / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D017403:In Situ Hybridization; D035683:MicroRNAs / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics* / Q000502:physiology; D029961:Zebrafish Proteins / Q000235:genetics* / Q000502:physiology; D000099291:Adducins
D020413:3' Untranslated Regions; D000199:Actins; D002148:Calmodulin-Binding Proteins; D035683:MicroRNAs; D020319:Oligodeoxyribonucleotides, Antisense; D029961:Zebrafish Proteins; D000099291:Adducins; C549612:MIRN143 microRNA, zebrafish