Collections > Electronic Theses and Dissertations > PRICKLE1 MUTATION CAUSES PLANAR CELL POLARITY AND DIRECTIONAL CELL MIGRATION DEFECTS ASSOCIATED WITH CARDIAC OUTFLOW TRACT ANOMALIES AND OTHER STRUCTURAL BIRTH DEFECTS
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Planar cell polarity (PCP) is controlled by a highly conserved pathway that regulates directional cell behavior during development. Here, we show that Bj mutant mice harboring a mutation in Prickle1 (Pk1), a core PCP component, exhibit a wide spectrum of developmental phenotypes with a common etiology involving cell polarity defects, including skeletal anomalies, cochlear patterning defects, and congenital cardiac anomalies. As a result, Bj mutants die at birth with cardiac outflow tract (OFT) malalignment. This is associated with a shortened OFT due to loss of polarized cell orientation and failure of second heart field cell intercalation in the dorsal pericardial wall required for OFT lengthening. OFT myocardialization was also disrupted with cardiomyocytes failing to align with the direction of cell invasion into the outflow cushions. The expression of genes mediating canonical and noncanonical Wnt signaling were altered. Also noted in the Bj mutants were shortened but widened bile ducts, along with reduced b-catenin expression indicating disruption in canonical Wnt signaling. Using an in vitro wound closure assay to examine cell migration behavior, we showed Bj mutant mouse embryonic fibroblast (MEF) cells are unable to establish polarized cell morphology or engage in directional cell migration. The actin cytoskeleton in mutant MEFs failed to align with the direction of wound closure. Unexpectedly, Pk1 mutants exhibited cilia defects, shown by reduction of primary cilia formation in Bj mutant MEFs and functional and structural defects associated with motile cilia in the tracheal epithelia. These findings are intriguing given the phenotypes exhibited by the Bj mutants are reminiscent of those seen in ciliopathies, suggesting Pk1 may play a role in regulation of cilia. Together these findings show Pk1 plays an essential role in PCP and the regulation of cell polarity and directional cell migration essential for development of the OFT and other tissues.