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Mayr T
,
Deutsch U
,
Kühl M
,
Drexler HC
,
Lottspeich F
,
Deutzmann R
,
Wedlich D
,
Risau W
.
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Signaling molecules of the Wnt gene family are involved in the regulation of dorso-ventral, segmental and tissue polarity in Xenopus and Drosophila embryos. Members of the frizzled gene family, such as Drosophila frizzled-2 and rat frizzled-1, have been shown encode Wnt binding activity and to engage intracellular signal transduction molecules known to be part of the Wnt signaling pathway. Here we describe the cloning and characterization of Fritz, a mouse (mfiz) and human (hfiz) gene which codes for a secreted protein that is structurally related to the extracellular portion of the frizzled genes from Drosophila and vertebrates. The Fritz protein antagonizes Wnt function when both proteins are ectopically expressed in Xenopus embryos. In early gastrulation, mouse fiz mRNA is expressed in all three germ layers. Later in embryogenesis fiz mRNA is found in the central and peripheral nervous systems, nephrogenic mesenchyme and several other tissues, all of which are sites where Wnt proteins have been implicated in tissue patterning. We propose a model in which Fritz can interfere with the activity of Wnt proteins via their cognate frizzled receptors and thereby modulate the biological responses to Wnt activity in a multitude of tissue sites.
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9178261
???displayArticle.link???Mech Dev
Fig. 3. (A) Purified fiz protein in Coomassie-stained SDS-PAGE. R denotes recombinant protein produced in CEF cells. Native protein as purified from BHK cells is marked N. (B) Western blot of samples in (A). The blot was probed with the rabbit polyclonal antiserum SA1804 specific for the mouse fiz (R) protein. The hamster fiz protein (N) did not react. (C) Silver-stained SDS-PAGE of purified BHKfiz protein. Samples were treated with (+) and without (â) β-mercapto-ethanol.
Fig. 4. (A) mfiz antagonizes the axis-inducing capacity of Xwnt-8. Embryos were injected with 10 pg of Xwnt-8 mRNA (left side) or 10 pg Xwnt-8 mRNA and 100 pg mfiz mRNA (right side) into the marginal zone of the two ventral blastomeres of a four-cell stage embryo. Representative views are shown, duplicated axes are indicated by arrow heads. (B,C) Expression of Xwnt-8 and mfiz in microinjected embryos. Embryos were injected at the four-cell stage embryo Xwnt-8 mRNA, mfiz mRNA, or both as indicated. To detect Xwnt-8 and mfiz in Western blotting, particularly high doses of 2 ng of each mRNA were injected. At the blastula stage when axis determination takes place, embryos were homogenized and lysates were probed for expression of Xwnt-8 by the myc-tag monoclonal antibody 9E10 (B) or for expression of mfiz with rabbit polyclonal mfiz antiserum SA1804 (C).
Fig. 5. Localization of mouse fiz mRNA in 7.5 dpc embryos. (A) Bright field illumination showing a sagittal section of the anterior region of a 7.5 dpc mouse embryo in the maternal decidua hybridized with 35S-labelled mfiz antisense RNA probe. (B) Dark field image of (A). (C) Dark field image of primitive streak area of the embryo. Abbreviations: Ec, ectoderm; En, endoderm; GC, giant cell; PS, primitive streak. Bar represents 40 μm.
Fig. 6. Localization of mouse fiz mRNA in 9.5 dpc embryos. (A) Bright field illumination of a frontal section through the rostral region of a 9.5 dpc mouse embryo hybridized with 35S-labelled mfiz antisense RNA probe. (B) Dark field image of (A). (C) Bright field illumination of a frontal section showing both the caudal and the head region of the embryo. (D) Dark field image of (C). (E) Enlargement of the neural tube area in (A). Highest expression of mfiz mRNA is marked by a white arrowhead. (F) Dark field image of (E). Abbreviations: FL, forelimb bud; FP, floor plate; HL, hindlimb bud; HM, head mesenchyme; MD, mesonephric duct; NE, neuroepithelium; NT, neural tube; RM, Reichert's membrane; So, somite. Bars represent 160 μm in (AâD) and 40 μm in (E,F).
Fig. 7. Localization of mouse fiz mRNA in 11.5 dpc embryos. (A) Dark field illumination of a sagittal section of a 11.5 dpc mouse embryo hybridized with 35S-labelled mfiz antisense RNA probe. (B) Dark field image of a parallel section probed with mfiz sense RNA. (C) Enlargement of the neural tube area in (A). Glial cells ensheathing dorsal roots and cells in the ventral area are marked by arrows and arrowheads, respectively. (D) Bright field image of (C). A stripe of mfiz mRNA-expressing cells in the medial region of the neural tube is marked by an arrowhead. Abbreviations: DA, dorsal aorta; DRG, dorsal root ganglion; NT, neural tube; UR, urogenital ridge; V, vertebra. Bars represent 80 μm in (A,B) and 40 μm in (C,D).
Fig. 8. Localization of mouse fiz mRNA in areas of bone formation of 17.5 dpc embryos. Bright field (A,D,G) and dark field illumination of selected areas of ossification in a 17.5 dpc. mouse embryo probed with 35S-labelled mfiz antisense RNA (B,E,H). Parallel sections probed with mfiz sense RNA are shown in dark field illumination in (C,F,I). In the cochlear capsule (AâC) mfiz mRNA is detected. (DâF) mfiz expression in the lamina cribosa and in the head of the mandible. Mfiz expression in the perichondrium of long bones is increased in the epiphysial growth plate (GâI). Abbreviations: EP, epiphysial growth plate; LC, zygoma; Ma, head of mandible. Bars represent 40 μm.
Fig. 9. Northern blot of mouse tissues at different stages of development. Total RNAs of postnatal tissues as well as RNAs of 9.5 dpc embryos and 15.5 dpc placenta were used. Arrows indicate a prominent transcript at 2.0 kb and transcripts of minor abundance of 2.6 and 4.8 kb. Blots were probed with 32P-labelled mfiz cDNA and reprobed with 32P-labelled β-actin cDNA for normalization.
