Atypical Protein Kinase C-Dependent Polarized Cell Division Is Required for Myocardial Trabeculation

Abstract

A hallmark of cardiac development is the formation of myocardial trabeculations exclusively from the luminal surface of the primitive heart tube. Although a number of genetic defects in the endocardium and cardiac jelly disrupt myocardial trabeculation, the role of cell polarization remains unclear. Herein, we demonstrate that atypical protein kinase C iota (Prkci) and its interacting partners are localized primarily to the luminal side of myocardial cells of early murine embryonic hearts. A subset of these cells undergoes polarized cell division with the cell division plane perpendicular to the heart's lumen. Disruption of the cell polarity complex by targeted gene mutations results in aberrant mitotic spindle alignment, loss of polarized cardiomyocyte division, and loss of normal myocardial trabeculation. Collectively these results suggest that in response to inductive signals, Prkci and its downstream partners direct polarized cell division of luminal myocardial cells to drive trabeculation in the nascent heart.

Development of the human heart

“…Cardiomyocytes in which the spindles are parallel with the lumen of the heart tube contribute to the lengthening of the heart tube, while cardiomyocytes with mitotic spindles in the direction of the lumen will contribute to the trabeculation (Le Garrec et al, ; Meilhac, Esner, Kerszberg, Moss, & Buckingham, ). When mitotic spindle orientation is disrupted, as is observed upon deletion of atypical protein kinase C (Prkc1), trabeculation formation is affected (Passer, van de Vrugt, Atmanli, & Domian, ). The layout of the initial trabeculations is defined by the concerted action of endocardially expressed Notch1 and Neuregulin 1.…”

Mechanisms of Trabecular Formation and Specification During Cardiogenesis

“…To determine whether OCD occurs during trabecular morphogenesis and trabecular specification, Domian’s and my labs used cellular and genetic tools to examine the cellular behaviors and the underlying genetic basis of trabecular initiation. We found that cardiomyocytes undergo OCD based on immunostaining, with about 40% of the mitotic cells aligning their spindle parallel to the myocardial epithelium, and about 40% of the mitotic cells aligning perpendicularly to the myocardium epithelium at about E8.5 23,24 . Furthermore, individual cardiomyocytes genetically labeled prior to trabeculation via the inducible Cre mediated brainbow / multicolor labeling system were traced and the labeled cells/clones were analyzed to reveal that most labeled cells undergo one round of division to yield two cells by 24 hours after tamoxifen induction.…”

“…These studies found that polarity complex proteins such as Par3, aPKC and Par6 are asymmetrically localized across the monolayer of the myocardial wall. Apical-basal polarity might be essential for oriented cell division during trabecular morphogenesis in the mouse 23,24 , while apical-basal polarity in zebrafish might maintain the epithelial features of the myocardium and might be essential for apical constriction and promoting the cardiomyocyte entry into the myocardium 22 .…”

Cardiac Regeneration

“…Trabeculae are ridge-shaped myocardial protrusions that are derived from the sub-endocardial myocardium. Although the key mechanistic events are still being elucidated, in mouse the process of trabeculation is thought to be initiated when a subset of sub-endocardial CMs alter their polarity from parallel to perpendicular relative to the chamber wall 114 . These CMs then proliferate and expand to form the trabeculae 115, 116, 117 .…”