P120. Nuclear localization of Prickle2 is required for the establishment of cell polarity during mouse early embryogenesis

In preimplantation mouse development, the first cell lineages to be established are the trophectoderm (TE) and inner cell mass (ICM). The divergence of the two first lineages of the mouse embryo is initiated at the 8-cell stage when blastomeres polarize during compaction. In this process, blastomeres acquire apico-basal polarity typified by apical localization of microvilli and acquisition of cytoplasmic polarity, including asymmetric distribution of E-cadherin and reorganization of the microtubule network. Subsequently, two major interrelated features of TE differentiation required for blastocoel formation include interacellular junction biogenesis and a directed ion transport system, mediated by Na+/K+ ATPase. Previous studies have shown that cell polarity complex (PAR-aPKC complex) regulates the orientation of cell cleavage planes, and cell polarity and adhesion, which altogether can influence the allocation of blastomeres to an outer or inner position in the blastocyst. However, their roles in regulating TE differentiation and blastocyst formation are still unclear. We focus on the roles of Prickle1 and Prickle2, the two mouse homologues of a Drosophila core planar cell polarity gene prickle, during mammalian embryogenesis. We previously reported that the deletion of Prickle1 resulted in early embryonic lethality, between E5.5 and E6.5 with the loss of apico-basal polarity of the epiblast and aberrant dorso-vental patterning of embryo (Tao, H. et al., Proc. Natl. Acad. Sci. USA 106, 2009). On the other hand, we found that Prickle2 knock out mice show that they die at E3.5-4.0 without forming the blastocyst cavity. Detailed analyses revealed that blastomeres after the compaction lost cell polarity that defines inner and outer cells, which gives rise to TE and ICM, respectively. We also found that Prickle2 is preferentially localized to nucleus in early blastomeres. Interestingly, inhibition of fernesylation blocked the nuclear localization and promoted cytoplamic localization of Prickle2, suggesting that the C-terminal fernesylation is essential for tethering Prickle2 to nucleus. Because the cell polarity is disrupted in the inhibitor-treated embryo, nuclear localization of Prickle2 is thought to be prerequisite to the establishment of the polarity. In this meeting, we will discuss about mechanisms that Prickle2 regulates apico-basal polarity during early mouse embryogenesis.