Mechanisms of planar cell polarity patterning by Prickle and Vangl and the control of collective cellular behaviors during tissue morphogenesis

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2017-08

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Butler, Mitchell Tyler

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Abstract

Planar Cell Polarity (PCP) signaling establishes asymmetric molecular patterns that control polarized cellular behaviors within the plane of a tissue or organ. This feature is conserved among metazoans and essential for proper development and tissue homeostasis. Owing to its important role in establishing tissue function, PCP signaling defects have been associated with diverse human pathologies, most notably birth defects. Tissue development is a dynamic process that requires the coordinated, temporal control of polarized cell behaviors, and here, I present the first vertebrate platform for the study of asymmetric PCP tissue patterning dynamics in vivo. Using Xenopus laevis as a model allows for relatively rapid and highly tractable studies of PCP patterning function in developing tissues, affording both subcellular analysis of PCP protein dynamics and multiple readouts for various planar- polarized cellular and tissue behaviors. I identified specific members of core PCP gene families that serve as faithful reporters for molecular planar polarity in the multiciliated epidermis and neural plate epithelia and uncover an essential role for Pk2 in the asymmetric PCP patterning of both of these tissues. I demonstrate that Pk2 function influences the progressive anterior localization of Dvl1 and posterior localization of Vangl1 in the epidermis, which when disrupted, results in severe ciliary orientation defects. Structure-function analysis reveals the conserved domains essential for Pk2 and Vangl1 asymmetry here. After characterizing the dynamic behaviors of apical cell-cell junctions that mediate convergent extension movements in the Xenopus neural plate, I also show that Pk2 and Vangl2 are dynamic and increasingly asymmetrically enriched at shrinking cell-cell junctions during cellular rearrangements. I present evidence that suggests the polarized enrichment of Pk2 promotes the polarized accumulation of the actomyosin contractional machinery that facilitates mediolateral cell intercalations. Lastly, I detail how PCP point mutant alleles identified in human neural tube defect patient studies impact polarized protein localization behavior. Together, these findings establish a robust in vivo platform for the quantitative study of vertebrate PCP signaling and demonstrate the potential of this platform for furthering our understanding of dynamic tissue patterning processes and the molecular etiology of human birth defects.

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