Nuclear localization of Prickle2 is required to establish cell polarity during early mouse embryogenesis

Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology (CDB), Chuo-ku, Kobe, Japan.
Developmental Biology (Impact Factor: 3.55). 02/2012; 364(2):138-48. DOI: 10.1016/j.ydbio.2012.01.025
Source: PubMed


The establishment of trophectoderm (TE) manifests as the formation of epithelium, and is dependent on many structural and regulatory components that are commonly found and function in many epithelial tissues. However, the mechanism of TE formation is currently not well understood. Prickle1 (Pk1), a core component of the planar cell polarity (PCP) pathway, is essential for epiblast polarization before gastrulation, yet the roles of Pk family members in early mouse embryogenesis are obscure. Here we found that Pk2(-/-) embryos died at E3.0-3.5 without forming the blastocyst cavity and not maintained epithelial integrity of TE. These phenotypes were due to loss of the apical-basal (AB) polarity that underlies the asymmetric redistribution of microtubule networks and proper accumulation of AB polarity components on each membrane during compaction. In addition, we found GTP-bound active form of nuclear RhoA was decreased in Pk2(-/-) embryos during compaction. We further show that the first cell fate decision was disrupted in Pk2(-/-) embryos. Interestingly, Pk2 localized to the nucleus from the 2-cell to around the 16-cell stage despite its cytoplasmic function previously reported. Inhibiting farnesylation blocked Pk2's nuclear localization and disrupted AB cell polarity, suggesting that Pk2 farnesylation is essential for its nuclear localization and function. The cell polarity phenotype was efficiently rescued by nuclear but not cytoplasmic Pk2, demonstrating the nuclear localization of Pk2 is critical for its function.

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    • "The mouse genome has four Prickle homologs, with Prickle1 and Prickle2 being most closely related to their Drosophila prototype, whereas Prickle3 and Prickle4 are fairly distant. Prickle1 and Prickle2 were reported to be essential for AB polarity of embryonic epiblasts since ablation of either in mice resulted in early embryonic lethality prior to gastrulation (Tao et al., 2012; Tao et al., 2009). An ENU-induced frameshift mutation in mouse Prickle1 resulted in limb defects and death shortly after birth (Yang et al., 2013), suggesting a yet to be explored late-stage Prickle1 function. "
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    ABSTRACT: Planar cell polarity (PCP) signaling plays a critical role in tissue morphogenesis. In mammals, disruption of three of the six ‘‘core PCP’’ components results in polarity-dependent defects with rotated cochlear hair cell stereocilia and open neural tube. We recently demonstrated a role of Prickle1, a core PCP molecule in Drosophila, in mammalian neuronal development. To examine Prickle1function along a broader developmental window, we generated three mutant alleles in mice. We show that the complete loss of Prickle1 leads to systemic tissue outgrowth defects, aberrant cell organization and disruption of polarity machinery. Curiously, Prickle1 mutants recapitulate the characteristic features of human Robinow syndrome and phenocopy mouse mutants with Wnt5a or Ror2 gene defects, prompting us to explore an association of Prickle1 with the Wnt pathway. We show that Prickle1 is a proteasomal target of Wnt5a signaling and that Dvl2, a target of Wnt5a signaling, is misregulated in Prickle1 mutants. Our studies implicate Prickle1 as a key component of the Wnt-signaling pathway and suggest that Prickle1 mediates some of the WNT5A-associated genetic defects in Robinow syndrome
    Full-text · Article · Sep 2014 · Biology Open
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    • "These structures are necessary for the proteins to localize to the nucleus, which is critical for the Prickle1 protein function as a transcription modulator (Bassuk et al., 2008; Mapp et al., 2011; Tao et al., 2012; Liu et al., 2013). In fact, recent data suggest that vertebrate Prickle1's function might in part be mediated by nuclear signaling (Mapp et al., 2011; Tao et al., 2012). We therefore hypothesized that Prickle1 plays a role in Wnt/PCP signaling partially through gene regulation, possibly a neo-functionalization of Prickle1. "
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