Abstract
ABSTRACTPlanar cell polarity (PCP) is controlled by a conserved pathway that regulates directional cell behavior. Here, we show that mutant mice harboring a newly described mutation termed Beetlejuice (Bj) in Prickle1 (Pk1), a PCP component, exhibit developmental phenotypes involving cell polarity defects, including skeletal, cochlear and congenital cardiac anomalies. Bj mutants die neonatally with cardiac outflow tract (OFT) malalignment. This is associated with OFT shortening due to loss of polarized cell orientation and failure of second heart field cell intercalation mediating OFT lengthening. OFT myocardialization was disrupted with cardiomyocytes failing to align with the direction of cell invasion into the outflow cushions. The expression of genes mediating Wnt signaling was altered. Also noted were shortened but widened bile ducts and disruption in canonical Wnt signaling. Using an in vitro wound closure assay, we showed Bj mutant fibroblasts cannot establish polarized cell morphology or engage in directional cell migration, and their actin cytoskeleton failed to align with the direction of wound closure. Unexpectedly, Pk1 mutants exhibited primary and motile cilia defects. Given Bj mutant phenotypes are reminiscent of ciliopathies, these findings suggest Pk1 may also regulate ciliogenesis. Together these findings show Pk1 plays an essential role in regulating cell polarity and directional cell migration during development.
Highlights
Planar cell polarity (PCP) is an evolutionarily conserved pathway that plays an important role in development
This would suggest a congenital heart defect known as an overriding aorta (OA) or double outlet right ventricle (DORV) (Fig. 1H-J)
In DORV, the aorta position is shifted rightwards to lie more than 50% over the right ventricle (RV), becoming aligned parallel to the pulmonary artery
Summary
Planar cell polarity (PCP) is an evolutionarily conserved pathway that plays an important role in development. Genetic analysis in Drosophila identified a group of interacting core PCP components that includes Van Gogh/Strabismus, Prickle, Frizzled, Dishevelled, Diego, and Flamingo (Devenport, 2014; Lawrence et al, 2007; Vladar et al, 2009) These proteins accumulate in asymmetrically localized complexes at proximal and. Received 28 October 2015; Accepted 21 January 2016 distal apical cell junctions where they establish molecular cell polarity along the forming tissue axes via cell-cell communication (Axelrod, 2009) These proteins are conserved in vertebrates, and mutations in them cause a wide spectrum of developmental anomalies (Wansleeben and Meijlink, 2011), including the misalignment of hair cells in the cochlea, neural tube closure, brain and skeletal defects, and congenital heart disease (Cui et al, 2013)
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