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Planar cell polarity (PCP) genes are essential for establishing planar cell polarity in both invertebrate and vertebrate tissues and are known to regulate cellular morphogenesis and cell movements during development. We focused on Prickle, one of the core components of the PCP pathway, and deleted one of two mouse prickle homologous genes, mpk1. We found that the deletion of mpk1 gene resulted in early embryonic lethality, between embryonic day (E)5.5 and E6.5, associated with failure of distal visceral endoderm migration and primitive streak formation. The mpk1(-/-) epiblast tissue was disorganized, and analyses at the cellular level revealed abnormal cell shapes, mislocalized extracellular matrix (ECM) proteins, and disrupted orientation of mitotic spindles, from which loss of apico-basal (AB) polarity of epiblast cells are suspected. Furthermore, we show mpk1 genetically interacts with another core PCP gene Vangl2/stbm in the epiblast formation, suggesting that PCP components are commonly required for the establishment and/or the maintenance of epiblast AB polarity. This was further supported by our finding that overexpression of DeltaPET/LIM (DeltaP/L), a dominant-negative Pk construct, in Xenopus embryo disrupted uniform localization of an apical marker PKCzeta, and expanded the apical domain of ectoderm cells. Our results demonstrate a role for mpk1 in AB polarity formation rather than expected role as a PCP gene.
Fig. 1. Expression pattern of mpk1 in postimplantation embryos. (A–D′) Expression of mpk1 transcripts in postimplantation embryos. (E and E′) Immunostaining for Pk1-specifc protein (red) within the cytoplasm of the E5.5+ epiblast. Nuclei were stained with Draq5 (green). ex, extraembryonic region; em, embryonic region; ect, ectoderm; ps, primitive streak; mes, mesoderm; ve, visceral endoderm; ac, proamniotic cavity. Anterior is to the left in B–D′. (Scale bars, 50 μm in B–D.)
Fig. 3. Marker analysis in the mpk1−/− mutant. Whole-mount in situ hybridization analysis of control (A–H) and mpk−/− mutant (A′–H′) embryos at E5.5–6.75. The number of analyzed mpk1−/− mutant embryos were following; E5.5, Hex, n = 5/5; Dkk1, n = 4/5; E6.5, Wnt3, n = 4/5; Bmp4, n = 5/6; E5.5, Wnt3, n = 4/5, Bmp4, n = 3/3; E5.5, Nodal, n = 3/3; E6.75, Nodal, n = 5/7. Arrowheads indicate the boundary between the embryonic and extraembryonic regions. Anterior is to the left in all panels.
Fig. 6. Overexpression of δP/L disrupts the apical and basolateral domains in the presumptive ectoderm of the Xenopus embryo. (A–D) δP/L caused partial pigment defects and/or expanded cells (B, asterisks) compared with controls (A). (C and D) FLAG-tagged β-globin or FLAG-tagged δP/L (1 ng each) was injected. (E) The effect of δP/L overexpression, which was scored blind, is shown. (F–K) Immunostaining with AB markers is shown in each panel. (F, H, and J) The β-globin-injected embryos were entirely normal. The number of analyzed δP/L overexpressing embryos were following; (G) n = 18; (I) n = 20; (K) n = 15. (G) The injection of δP/L caused the abnormal localization of PKCζ in the apical region. Inset is another image. These images are of single planes of optical sections (F and G). (I) The injection of δP/L caused the ectopic localization of ZO-1 to the basolateral side (red arrowheads). (K) The localization of β1-integrin to the basolateral region was not altered by the injection of δP/L. (L) The quantification of namely uneven localization of PKCζ at the apical membrane in the δP/L-injected embryo compared with the control (n = 8, each injected cells) (see SI Materials and Methods). (M) The quantification of ectopic ZO-1 in the δP/L-injected embryo compared with β-globin-expressing cells (embryos); n = 291 (13), 196 (7), 197 (10), δP/L-expressing cells (embryos); n = 110 (9), 169 (10), 204 (12). This experiment was carried out 3 times. Error bars, the s.e.m.; asterisk denotes a significant difference (P < 0.05), compared with the control. Apical is at the top (A–D, F–K).
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