Dickinson AJ , Sive HL .

R21 DE017758-01 NIDCR NIH HHS

	Fig. 2. In situ hybridization of frzb-1 and crescent mRNA during neurula and early tailbud stages. (A-H′) In situ hybridization of frzb-1 (A-D) and crescent (E-H) during neurula and early tailbud stages. frzb-1 and crescent are stained purple/blue, the cement gland marker (XCG), dark red and the CNS-specific marker (nrp1), light orange. Arrows indicate the presumptive primary mouth. cg, cement gland. A-H are frontal views, scale bars: 200 μm; A′-H′ are sagittal sections with anterior to the left, scale bars: 130 μm.
	Fig. 3. frzb-1/crescent loss-of-function analysis. (A) frzb-1 and crescent loss of function using antisense morpholinos, and rescue by frzb-1 mRNA in whole embryos. Frontal views are shown, assayed at stage 40 in two to four independent experiments. cg, cement gland. Scale bars: 250 μm. Open primary mouth, black dotted line; closed stomodeum, yellow dotted line. (a-d) Morpholino injection (60-80 ng/embryo). (a) Control morpholino results in a normal primary mouth (100%, n=121). (b) Two frzb-1 start site morpholinos result in a very small stomodeum (97%, n=57). (c) A crescent splice blocking morpholino results in a smaller primary mouth (100%, n=50). (d) frzb-1 morpholinos (15 ng/embryo of each) and crescent morpholino (30 ng/embryo) result in neither stomodeum nor primary mouth (99%, n=66). (e-h) Rescue: 60 ng morpholino and 200 pg mRNA was injected/embryo. (e) Control morpholinos plus GFP mRNA have no effect (100%, n=45). (f) Control morpholinos with frzb-1 mRNA results in a normal primary mouth (100%, n=33). (g) frzb-1/crescent morpholinos plus GFP mRNA result in neither a stomodeum nor a primary mouth (94%, n=32). (h) frzb-1/crescent morpholinos plus frzb-1 mRNA results in a primary mouth opening (86%, n=55). Arrows indicate the primary mouth or region where it would form. (B) The primary mouth anlage is correctly specified. (a,b) Analysis of pitx3 expression by in situ hybridization in (a) control and (b) frzb-1/crescent morphant embryos. Note that pitx3 expression is present in the morphant. Scale bars: 200 μm. (c,d) Analysis of vgl-2 expression by in situ hybridization in (c) control and (d) frzb-1/crescent morphant embryos. Note that vgl-2 expression it is present in the morphant. Arrows indicate the primary mouth anlage. Scale bars: 200 μm. (C) Localizing morphant and wild-type tissue using face transplants. (a) Schematic of experimental design: donor morphant tissue (FITC labeled) was transplanted to uninjected sibling recipients. (b) The primary mouth is normal when donor tissue is derived from embryos injected with control morpholinos (100%, n=9). (b′) Overlay of b with FITC fluorescence, indicating the location of the donor tissue in the recipient. (c) When donor tissue is derived from frzb-1/crescent morphants, 83% of recipients do not form a primary mouth opening and 17% form a small stomodeum (n=12). These embryos also have abnormalities in surrounding tissues, pigment cells do not migrate normally and the face appears thinner. (c′) Overlay of c with FITC fluorescence. (d) Schematic of experimental design: donor wild-type tissue was transplanted to morphants. (e) The primary mouth is normal when recipients are injected with standard control morpholinos (100%, n=7). (e′) Overlay of e with FITC fluorescence. (f) When recipients are frzb-1/crescent morphants, a primary mouth is present (80%, n=15). Although the primary mouth is not a normal shape, a deep invagination forms, followed by perforation. (f′) Overlay of f with FITC fluorescence.
	Fig. 1. Schematic summarizing microarray screen for genes whose expression is enriched in the primary mouth anlage. (A) Regions microdissected for RNA collection: anterior dorsal region (AD, dark gray), ventral region including the cement gland (CG+V, light gray) and the presumptive primary mouth (PMo, red). Foregut epithelium is shown in yellow. (B) Expression of frzb-1 and ef1-alpha in the primary mouth (red) relative to flanking regions (88%, microarray; 71%, qRT-PCR).
	Fig. 4. Temporal and spatial overexpression of wnt-8 under control of a heat-shock promoter element (HSE) and using ectoderm transplants. Frontal views are shown, assayed at stage 40 in two to three independent experiments. Open primary mouth, black dotted line; cg, cement gland; pSGH2, ISceI-GFP-HSE plasmid. Arrows indicate the primary mouth or region where it would form. Scale bars: 250 μm. (A) Schematic showing prediction that if Frzb-1/Cresent inhibits Wnt signaling, increased Wnt-8 would phenocopy loss of Frzb-1/Crescent. (B) Injected with GFP::HSE followed by heat shock at either stage 17 or 25 has no effect on primary mouth formation (90%, n=50). (C) Injection of GFP::HSE::wnt-8 and heat shock administered at stage 17 results in neither a stomodeum nor a primary mouth (97%, n=65). (D) Injection of GFP::HSE::wnt-8 and heat shock administered later (stage 25-28) results in a normal primary mouth (47%) or a slightly smaller one (53%, n=32). (E) Schematic of experimental design using ectoderm transplants. (F) Control (GFP::HSE): when heat shock was administered at stage 17 and transplants performed at stage 24, recipients form a primary mouth (100%, n=12). The same is true if heat shock is administered at stage 24 and transplants are performed at stage 28 (n=10). (G) GFP::HSE::wnt-8: when heat shock was administered at stage 17 and transplants performed at stage 24, 83% of the recipients do not form a stomodeum or a primary mouth (n=12). (H) When the experiment in G was performed later, 88% formed a normal primary mouth (n=9).
	Fig. 5. Frzb-1 and Dkk-1 regulate the same pathway. (A) Temporal overexpression of frzb-1 and dkk-1 during neurula (stage 17). b′,d′,e′ are sagittal optical sections (anterior to the left). Assayed at stage 40, two independent experiments. Open primary mouth, black dotted line; closed stomodeum, yellow dotted line; bracket indicates the position of the primary mouth or stomodeum; pSGH2, ISceI-GFP-HSE plasmid. Scale bars: 250 μm. (a) Schematic of experimental design. (b) Control (GFP::HSE) results in a normal primary mouth (90%, n=66), frontal view. (b′) Embryo treated as in b with a normal primary mouth. (c) Schematic showing the prediction that increased Frzb-1 would mimic overexpression of Dkk-1. (d) Injection of GFP::HSE::frzb-1 results in a larger stomodeum, frontal view (48%, n=50). (d′) Embryo treated as in d, showing increased stomodeal surface. (e) Injection of GFP::HSE::dkk1 results in a larger stomodeum, frontal view (53%, n=38). (e′) Embryo treated as in e has an increased stomodeal surface. (B) Rescue of the primary mouth in frzb-1/crescent morphants with dkk-1 mRNA. Frontal views, assayed at stage 40 in duplicate. Black arrow, primary mouth; cg, cement gland. Scale bars: 250 μm. (a) Schematic of experimental design. (b) The primary mouth is absent when donor tissue is derived from embryos injected with frzb-1/crescent morpholinos and GFP mRNA (90%, n=10). (b′) Overlay of b with FITC fluorescence, indicating the location of the donor tissue in the recipient. (c) When donor tissue is derived from embryos injected with frzb-1/crescent morpholinos and dkk-1 mRNA, 66% of recipients form a primary mouth and 33% form a large stomodeum with no opening (n=12). (c′) Overlay of c with FITC fluorescence.
	Fig. 6. Frzb-1 does not regulate Wnt/PCP or Bmp signaling. Frontal views, assayed at stage 40, from 2-3 independent experiments. Open primary mouth, black dotted line; closed stomodeum, yellow dotted; cg, cement gland. Black arrows indicate the primary mouth or region where it would form. Scale bars: 250 μm. (A) Schematic showing the prediction that if frzb-1 inhibits the PCP pathway, JNK inhibition would mimic frzb-1 overexpression. (B) Treatment with 1% DMSO results in a normal primary mouth (100%, n=15). (C) Treatment with 20 μm SP600125 results in neither a stomodeum nor a primary mouth (100%, n=15). (D) Schematic showing the prediction that if frzb-1 inhibits BMP signaling, increased Chordin would phenocopy frzb-1 overexpression. (E) The control GFP::HSE results in a normal primary mouth (100%, n=30). (F) GFP::HSE:chrd results in a small stomodeum (63%, n=32).
	Fig. 7. Laminin persists in the primary mouth region when Frzb-1/Crescent are depleted or when wnt-8 is overexpressed. Sagittal sections (anterior to the left) assayed at stage 35-37, in 2-3 independent experiments. Laminin is immunolabed green, nuclear propidium iodide, red; cement gland is outlined by a dotted gray line. Panels denoted by primes are tracings of Laminin immunolabeling (green). Bracket indicates the presumptive primary mouth; cg, cement gland. Scale bars: 170 μm. (A) Laminin persistence in frzb-1/crescent morphants is specific. (a) Control morpholino and GFP mRNA results in a normal absence of Laminin in the presumptive primary mouth (100%, n=10). (b) In frzb-1/crescent morphants (also injected with control GFP mRNA), Laminin persists in the primary mouth region (87%, n=10). Note that similar phenotypes were seen in morphants injected without GFP mRNA. (c) Control morpholino and frzb-1 mRNA (200 pg) results in a normal absence of Laminin in the presumptive primary mouth (n=10). (d) Co-injection of frzb-1/crescent morpholinos and frzb-1 mRNA restores the absence of Laminin in 70% of morphants (n=10). (B) Laminin persists in embryos locally depleted of frzb-1/crescent. (a) Schematic of the experimental design. (b) Recipients receiving tissue injected with control morpholino and GFP mRNA have a normal absence of Laminin (100%, n=7). (c) Eighty-nine percent of recipients receiving tissue from frzb-1/crescent morphants have persistent Laminin (n=9). (C) Temporal and spatial overexpression of Wnt-8 results in persistent Laminin. (a) Schematic of the experimental design. (b) Recipients receiving tissue injected with GFP::HSE have a normal absence of Laminin (91%, n=11). (c) Seventy-five percent of recipients receiving tissue from embryos injected with GFP::HSE::wnt-8 have persistent Laminin (n=12). (D) Wnt signaling regulates the expression of basement membrane components. Schematic depicts experimental design. Results are an average of two independent experiments. (a) Increased frzb-1 results in fibronectin mRNA that is 45% of the control level, laminin-γ1 mRNA that is 48% of the control level andβ 1-integrin that is 112% of the control level (n=20). (b) Temporally increased wnt-8 results in fibronectin mRNA that is 232% of the control level, laminin-γ1 mRNA that is 170% of the control level and β1-integrin mRNA that is 93% of the control levels (n=20).
	Fig. 8. Model of frzb-1/crescent function in primary mouth formation. At neurula stages (stage 17-22), frzb-1 and crescent are expressed in a subset of cells that will form the primary mouth (purple). In these cells, frzb-1 and crescent inhibit Wnt signaling, which in turn prevents the continued synthesis of proteins Laminin and Fibronectin. Without such proteins, the basement membrane integrity is lost and by early tailbud stages (stage 24-26) it disappears. The dissolution of the basement membrane leads to subsequent stages of primary mouth development including cell death, invagination, thinning and finally perforation. frzb-1/crescent-expressing cells are colored purple; ectoderm, blue; endoderm, yellow. The basement membrane (BM) is indicated by a black line; cg, cement gland.
	Fig. S1. Microarray analysis. (A) Frontal view of embryos labeled by in situ hybridization for genes indicated. Arrows indicate the presumptive primary mouth. cg, cement gland. Scale bars: 200 . cDNAs used for making in situ probes are vgl-2 (GA# BC056001, image clone 4930090, Open BioSystems), CPN (GA# BC059995, image clone 4030455, Open Biosystems), pitx-3 GA# AF297713.1, provided by Hollemann (Pommereit et al., 2001) and six-1 GA# AF279254, provided by Moody (Pandur and Moody, 2000). (B) Expression levels of genes from Table S1, as determined by microarray (M) and qRT-PCR (R). Shading and colors match scheme shown in Fig. 1, in which the anterior dorsal region (AD) is shaded dark gray, the cement gland and ventral region (CG+V) light gray, and the presumptive primary mouth (PMo) is colored red. (C) Expression of Wnt pathway components in the primary mouth (red) relative to the anterior dorsal region (AD; dark gray), and a ventral region, including the ventral half of the cement gland (CG+V; light gray) as determined by microarray. The expression level of each gene was plotted relative to each other so that a single bar represents the total expression in all three regions, scaled to 100. In the primary mouth anlage expression of wnt-8, wnt-8b, wnt-3a and wnt-2 is significantly depleted (<6% relative to the flanking regions) and expression of wnt-4, β-catenin, axin and the Frizzled receptors frz-3 and frz-9 are also depleted (<20% relative to the flanking regions). Other Wnt inhibitors, dkk-1 and wif-1, are enriched (>57% relative to the flanking regions).
	Fig. S2. In situ hybridizations to show expression patterns sfrps during neurula and early tailbud stages.sfrp1 (A-D), sfrp2 (E-H) and sfrp5 (I-L) are labeled purple/blue, whereas the cement gland marker, XCG, is labeled orange. A, C and E are frontal views; B, D and F are sagittal sections (anterior to the left) of the same stage; G-L are frontal views. Arrows indicate the presumptive primary mouth. cg, cement gland. Scale bars: 200 . cDNAs used for making in situ probes were obtained from Open Biosystems; sfrp-1 (GA# BC106360, image clone 7392081), sfrp-2 (GA# BC044687, image clone 5571003) and sfrp-5 (GA# BC082632, image clone 5512233).
	Fig. S3. Characterizing the morpholino phenotype. (A, parts a,b) Whole embryo phenotype. (a) frzb-1/crescent morphants at stage 23-24 compared with control morpholino-injected embryo. Note the overall similarity in the embryos, suggesting that the positioning and specification of many of the anterior structures are normal. (b) frzb-1/crescent morphants at stage 40-41 compared with control morpholino-injected embryo. Note the curved axis and reduced head structures. Scale bars: 1000 (c,d) Alcian Blue staining of cartilage at stage 45 in (c) control embryos, and (d) frzb-1 and crescent morphants. Note the almost complete lack of Alcian Blue staining in the morphants. Scale bars: 340 . (e,f) Axon tracts of the CNS at stage 40 were visualized by acetylated tubulin immunohistochemistry in (e) controls and (f) frzb-1/crescent morphants. Note the unorganized axon tracts in frzb-1/crescent morphants. Scale bars: 370 . (g,h) Phalloidin labeling of somites at stage 45 in (g) controls and (h) frzb-1/crescent morphants, using F-actin labeling with Phalloidin conjugated to Alexa Fluor 488. Scale bar: 1200 . Insets show a 100magnification of the somites, note the unorganized muscle fibers in frzb-1/crescent morphants. Scale bar: 1200 . (B, parts a,b) Embryos and tadpoles were processed for terminal deoxynucleotidyl transferase-mediated dTP nick-end labeling (TUNEL) as described (Dickinson and Sive, 2006), using the Apoptag kit (Chemicon). TUNEL labeling (green) in the primary mouth region of (a) control and (b) frzb-1/crescent morphants; embryos were counterstained with propidium iodide (red). Note that there are few TUNEL-positive cells in the presumptive primary mouth at stage 24-26, and no observable difference in frzb-1/crescent morphants (n=5; two experiments, not quantified). Scale bars: 100 . (c,d) Phosho-histone3 (pH3) immunohistochemistry (green) using a polyclonal anti-phosphohistone3 antibody diluted 1:1000 and a secondary goat anti-rabbit Alexa Fluor-conjugated antibody diluted 1:500, counterstained with propidium iodide (1:1000). (c) Control. (d) frzb-1/crescent morphants have similar amounts of pH3-positive cells to controls (6.33%, no significant difference) in the presumptive primary mouth regions (four stages examined, n=5 at each stage, one stage in one experiment quantified). Arrows indicate the presumptive primary mouth. cg, cement gland. Scale bars: 100 .
	Fig. S4. Requirement of the frzb-1/crescent expression domain for primary mouth formation. Fate mapping has shown that the region expressing frzb-1 becomes the primary mouth (data not shown) (Dickinson and Sive, 2006). Removing the superficial layers of ectoderm does not affect primary mouth formation (Dickinson and Sive, 2006), probably because frzb-1/crescent expression is restricted to deeper layers. We tested whether the frzb-1/crescent expression domain was required for primary mouth formation by performing extirpations. Arrows indicate the presumptive primary mouth; cg, cement gland. (A-C) Schematic of dissections at stage 23-24 depicting anterior ectoderm (blue), foregut epithelium (yellow), and dissected regions (dotted red box). (D-F) frzb-1 in situ hybridization immediately after dissection. frzb-1, purple/blue; xcg, orange. Scale bars: 200 . (D) In un-operated embryos, the frzb-1 expression domain is normal 100% (n=10). (E) In 91% of embryos with superficial extirpations, the frzb-1 expression domain is normal (n=11). (F) Embryos receiving the deep extirpations rarely (8.3%) contain significant frzb-1 expression (n=12) (G-I) Frontal view of representative embryos at stage 40, showing the effect of the extirpations on the formation of the primary mouth; the opening is outline by a dotted black line. Scale bars: 250 . (G) 100% of un-operated embryos have a normal primary mouth (n=10). (H) 100% of embryos with the superficial ectoderm removed have a normal primary mouth (n=10). (I) 90% of embryos having the deep ectodermal extirpations do not form a primary mouth (n=10).
	Fig. S5. Measurement of Wnt signaling in the primary mouth region using β-catenin protein and activity as a readout. Schematic depicts the experimental design. Embryos at the 1-cell stage were injected with (A) frzb-1 mRNA or GFP mRNA or (B) frzb-1 RNA or GFP RNA plus the TOPFLASH plasmid and the renilla reference plasmid, then at stage 20-22 the primary mouth and area just surrounding it was dissected from 10 embryos. Tissue was pooled and processed for (A) western blot or (B) the TOPFLASH assay. The western blot shows a 27% decrease in β-catenin protein in tissue collected from embryos injected with frzb-1 mRNA compared with controls (n=10, two experiments). The TOPFLASH assay shows an 88% decrease in luciferase activity in tissue collected from embryos injected with frzb-1 mRNA compared with controls injected with GFP (n=10, two experiments, s.d.=1.42).
	cpn1 (carboxypeptidase N, polypeptide 1) gene expression in a Xenopus laevis embryo, NF stage 24, assayed by in situ hybridization, anterior view, dorsal up.
	frzb (frizzled related protein) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 17, (A) anterior view, dorsal up., and (A') in midsaggital section, anterior left, dorsal up. Co-staining: muc2 (mucin 2, oligomeric mucus/gel-forming) marks cement gland (cg), and nrp1( neuropilin 1) marks brain in light orange; arrows indicate the position of the presumptive primary mouth.
	frzb (frizzled related protein) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 24, (B) anterior view, dorsal up, and (B') in section. Co-staining: muc2 (mucin 2, oligomeric mucus/gel-forming) marks cement gland (cg), and nrp1( neuropilin 1) marks brain and eyes in light orange.; arrows indicate the position of the presumptive primary mouth.
	frzb (frizzled related protein) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, (C) anterior view, dorsal up, and (C') in midsaggital section, anterior left, dorsal up.. Co-staining: muc2 (mucin 2, oligomeric mucus/gel-forming) marks cement gland (cg), and nrp1( neuropilin 1) marks brain and eyes in light orange.; arrows indicate the position of the presumptive primary mouth.
	frzb (frizzled related protein) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 28, (D) anterior view, dorsal up, and (D') in midsaggital section, anterior left, dorsal up. Co-staining: muc2 (mucin 2, oligomeric mucus/gel-forming) marks cement gland (cg), and nrp1( neuropilin 1) marks brain and eyes in light orange.; arrows indicate the position of the presumptive primary mouth.

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