Planar Cell Polarity Signaling in Mammalian Cardiac Morphogenesis

Abstract

The mammalian heart is the first organ to form and is critical for embryonic survival and development. With an occurrence of 1%, congenital heart defects (CHDs) are also the most common birth defects in humans, and major cause of childhood morbidity and mortality (Hoffman and Kaplan in J Am Coll Cardiol 39(12):1890-1900, 2002; Samanek in Cardiol Young 10(3):179-185, 2000). Understanding how the heart forms will not only help to determine the etiology and to design diagnostic and therapeutic approaches for CHDs, but may also provide insight into regenerative medicine to repair injured adult hearts. Mammalian heart development requires precise orchestration of growth, differentiation, and morphogenesis to remodel a simple linear heart tube into an intricate, four-chambered heart with properly connected pulmonary artery and aorta, a structural basis for establishing the pulmonary and systemic circulation. Here we will review the recent advance in our understanding of how the planar cell polarity pathway, a highly conserved morphogenetic engine in vertebrates, regulates polarized morphogenetic processes to contribute to both the arterial and venous poles development of the heart.

Apical Restriction of the Planar Cell Polarity Component VANGL in Pancreatic Ducts Is Required to Maintain Epithelial Integrity

“…VANGL, a component specific to the PCP, plays a central role in the establishment of the core protein complex (Hatakeyama et al, 2014). Mutations in the VANGLs underlie a broad spectrum of developmental disorders in humans (Butler and Wallingford, 2017), such as neural tube defects (Iliescu et al, 2014;Merello et al, 2015), renal (Papakrivopoulou et al, 2018;Schnell and Carroll, 2016), heart (Yuan et al, 2014;Li and Wang, 2018), and lung diseases (Yates and Dean, 2011). Moreover, recent studies have shown that VANGL2 is consistently upregulated and amplified in breast, ovarian, and uterine carcinomas (Hatakeyama et al, 2014), and a tumorigenic function has been established in rhabdomyosarcoma (Hayes et al, 2018).…”

Planar cell polarity signaling regulates polarized second heart field morphogenesis to promote both arterial and venous pole septation

“…5B, B″), despite severe disruption of SpM-SHF deployment, in contrast to Tbx1 and Nkx2.5 mutants (Francou et al, 2017). Therefore, it seems that OFT-oriented cell elongation and multicellular actomyosin cables may not be caused by SpM-SHF deployment per se but due to other sources, such as cardiac contraction (Francou et al, 2017) or a pulling force from the rostral SpM-SHF due to increased cell cohesion (Cortes et al, 2018;Francou et al, 2014;Li et al, 2016;Li and Wang, 2018). Irrespective of the source, the OFT-oriented mechanical signal may provide a key guidance cue, which functions together with Wnt5a/PCP to deploy SpM-SHF cell directionally towards the OFT (see below).…”

Planar cell polarity in organ formation

“…Additionally, data from Drosophila indicate that PCP is regulated by the asymmetric distribution of different core PCP proteins at the cell membranes and that this is a pre-requisite to establishing planar polarity across fields of cells [3]. This asymmetric distribution of PCP proteins is not always as prominent in vertebrate organogenesis, but has been observed in several organs including the cochlea, skin epidermis, heart and more recently in the papilla of the tongue and kidneys [7][8][9][10][11]. The asymmetric distribution of PCP proteins may be triggered by one or more inputs, e.g.…”

“…Some of the earliest studies of the PCP pathway in mammalian organ formation highlighted its role in skin and kidney development but there is now an increasing list of other organs for which the PCP pathway has been shown to be required, this includes the heart, lungs, eyes, testes, teeth and tongue among others [7,9,[14][15][16][17][18][19]. A recurrent theme in organogenesis is that the PCP…”