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.

Figure 1. The canonical Wnt and the planar cell polarity pathway

Dishevelled (Dsh/Dvl) and Frizzled (Fz) and important components of both the canonical Wnt and the PCP pathway. In the Wnt pathway, binding of Wnt to Fz and it co-receptors Arrow/Lrp5/6 promotes Dsh/Dvl to stablize β-catenin, which then enters the nucleus to regulate gene transcription. In the PCP pathway, however, Dsh/Dvl and Fz interact with PCP-specific core proteins, such as Van Gogh (Vang), and act in a β-catenin independent manner to coordinate cell polarity or regulate directional cell behavior during convergent extension (CE) tissue morphogenesis.

Figure 2. Current models on PCP signaling in OFT morphogenesis

(A) The “pushing force” model argues that Wnt5a activates Dvl-mediated PCP signaling to promote CE-like oriented cell intercalation in the caudal SpM region of the SHF to generate a morphogenetic force that “push” SHF cell rostrally into the OFT. (B) Disruption of this morphogenetic force in Wnt5a and Dvl1/2 mutants reduced SHF cell deployment, leading to OFT shortening and subsequent morphogenesis defects. (C) The “transition zone polarization” model argues that PCP signaling maintains proper epithelial polarization and organization in SHF-derived cells prior to their terminal differentiation into myocardium at the distal region of the OFT. Disruption of Vangl2 perturbs polarization and epithelial organization of cells in the transition zone. These defects in turn cause OFT thickening at the expense of lengthening, and consequently, OFT shortening and mis-alignment with the ventricles.

Figure 3. An updated model for SHF cell deployment

At the caudal SpM, Wnt5a-initiated PCP signaling may regulate both cell cohesion and oriented cell intercalation to promote polarized morphogenesis of the SpM-SHF, thereby generating a bi-directional pushing force to deploy SHF cells to both the arterial and venous pole of the heart for OFT and DMP formation, respectively. In the rostral SpM, loss of Wnt5a expression will allow cell cohesion to increase when SHF cells approach the OFT and undergo myocardial differentiation. This spatially regulated cell cohesion may in turn create a directional “pulling force”, which acts together with the caudally-generated pushing force to more efficiently deploy SHF cells rostrally into the OFT.