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Cardiac trabeculation is one of the essential processes required for the formation of a competent ventricular wall, whereby clusters of ventricular cardiomyocytes (CMs) from a single layer delaminate and expand into the cardiac jelly to form sheet-like projections in the developing heart (Samsa et al., 2013). Several congenital heart diseases are associated with defects in the formation of these trabeculae and lead to embryonic lethality (Jenni et al., 1999; Zhang et al., 2013, Jenni et al., 2001; Towbin 2010). It has been experimentally shown that lack of Nrg1/ErbB2/ErbB4, Angipoetin1/Tie2, EphrinB2/B4, BMP10, or any component of the Notch signaling pathway can cause defective trabeculation. Moreover, changes in blood flow and/or contractility can also affect trabeculation (Samsa et al., 2013). Together, these observations demonstrate that cardiac trabeculation is a highly dynamic and regulated process.
Trabeculation is a morphogenetic process that requires control over cell shape changes and rearrangements, similar to those observed during EMT. Epithelial cells within an epithelium are polarized and establish cell-cell junctions with the neighboring cells (Ikenouchi et al., 2003; Ferrer-vaquer et al., 2010), thus epithelial cell polarity is an important feature to maintain cell shape and tissue structure. During developmental processes such as cell migration and cell division or in disease states epithelial polarity might be disrupted. As a consequence of this alteration, cells lose their tight cell-cell adhesions, undergo cytoskeletal rearrangements, change their shape and gain migratory properties becoming mesenchymal cells (Micalizzi et al., 2010). In epithelial cells, apicobasal polarity is regulated by a conserved set of core complexes, including the PAR, Scribble and Crumbs complexes (Kemphues et al., 1988; Bilder and Perrimon, 2000; Teppas et al., 1984). The polarity proteins composing these complexes interact in a well organized and coordinated-manner creating molecular asymmetry along the apicobasal axis of the cell. In turn, this crosstalk regulates the maturation and stabilization of the junctions between cells and cytoskeleton in order to strengthen cell polarization (Roignot et al., 2013). Amongst the different polarity complex, Crumbs has been shown to be a key regulator of apicobasal polarity during development in both vertebrates and invertebrates (Tepass et al., 1990; Fan et al., 2004).
Here, taking advantage of zebrafish as a model organism, I study in vivo at single cell resolution changes in CM apicobasal polarity during cardiac trabeculation. Moreover, I show which factors regulate CM apicobasal polarity during this process. In addition, I dissect the role of the polarity complex Crumbs in regulating CM junctional rearrangements and the formation of the trabecular network.
The role of the homeobox transcription factor Meis2b in zebrafish heart development and asymmetry
(2018)
Zebrafish heart development: The heart of the zebrafish is the first organ to form and function during embryonic development, and is composed by one atrium and one ventricle. Between 5-17 somites stage, the cardiomyocyte precursors form the bilateral cardiac fields in the anterior lateral plate mesoderm (ALMP); where the endocardial precursors are located anterior to the cardiac fields (Zeng, Wilm et al. 2007). Then, the pools of endocardial andmyocardial precursors fuse at the midline and form the heart disc; where atrial cardiomyocytes are located around, the ventricular cardiomyocytes are located in the centerof the heart disc, and the future endocardium is located in a ventral position relative to the cardiomyocytes (Bakkers 2011). After the heart disc is formed, the cardiomyocyte progenitors start to migrate and rotate asymmetrically to form the heart tube (de Campos-Baptista, Holtzman et al. 2008, Rohr, Otten et al. 2008, Smith, Chocron et al. 2008). This process is followed by a rightward bending of the heart tube, and the arterial and venous poles rotate at different speed and directions (a process known as heart looping) (Smith, Chocron et al. 2008). The heart looping process results in a ventricle located on the right side and a more posterior atrium located on the left side with respect to the midline; at this point the atrium and ventricle are separated by a fine segment called the atrioventricular canal, where the valves will be formed (Staudt and Stainier 2012). The second heart field (SHF) is a pool of cardiac progenitors that are specified later during the formation of the heart disc and until the heart looping stages. The SHF contributes withcells to the distal side of the ventricle, the outflow and inflow tracts, and is important for the specification of the cardiac conduction system (de Pater, Clijsters et al. 2009, Hami, Grimes et al. 2011, Zhou, Cashman et al. 2011, Witzel, Jungblut et al. 2012, Guner-Ataman, Paffett-Lugassy et al. 2013)....