Cervino AS , Moretti B , Stuckenholz C , Grecco HE , Davidson LA , Cirio MC .

Doctoral Fellowship Program Consejo Nacional de Investigaciones Científicas y Técnicas, NICHD R01 HD044750 NIH HHS , 2013-1301,2014-3658 Fondo para la Investigación Científica y Tecnológica, 20020170100755BA Secretaría de Ciencia y Técnica, Universidad de Buenos Aires, PICT-2013-0381 Agencia Nacional de Promoción Científica y Tecnológica of Argentina

	Figure 1. Fry loss-of-function and rescue experiments. 4-cell stage Xenopus embryos were injected into both dorsal blastomeres as indicated and fixed at stage 30 (St. 30). (a) Uninjected embryo. (b) Standard Control morpholino (St-MO) (15 ng) injected embryo. (c,d) fry-MO (15 ng) injected embryos exhibiting “Shortened axis” or “Shortened axis & Head-less” phenotypes, respectively. (e) Rescue experiment; fry-MO (15 ng) + FD + LZ mRNA (800 pg) co-injected embryo. (f) FD + LZ mRNA (800 pg) injected embryo. Representative embryos are shown. (g) Quantitation of the percentage of embryos showing the different phenotypes: “Not affected”, “Shortened axis” or “Shortened axis & Head-less”. Embryos were scored as “Shortened axis” when presented < 80% of the body length relative to the average length of control embryos. N: number of independent experiments, n: number of embryos. Data in graph is presented as mean. Statistical significance was evaluated using Chi-square test (****,††††p < 0.0001). * represents the comparison to the uninjected group and † represents the comparison to the fry-MO injected group.
	Figure 2. Dorsal fry-depletion affects early expression of organizer genes and causes gastrulation defects. (a–l’’) In situ hybridization of Xenopus embryos at the indicated stages. (a–a’’) Expression of otx2 in the presumptive prechordal mesoderm. (a) Uninjected embryo (N = 2; n = 33). (a’) St-MO injected embryo (N = 2; n = 33; 6% with reduced expression domain) (a’’) fry-MO injected embryo (N = 2; n = 26; 85% with reduced expression domain). (b,c’’) Expression of gsc in the presumptive prechordal mesoderm. (b) Uninjected St.10 embryo (N = 3; n = 98). (b’) fry-MO injected St.10 embryo (N = 2; n = 34; 6% with reduced expression domain) (b’’) fry-MO injected St.10 embryo (N = 3; n = 74; 78% with reduced expression domain). Dorsal is oriented to the top. (c) Uninjected St.13 embryo (N = 3; n = 60). (c’) St-MO injected St.13 embryo (N = 2; n = 30; 10% with abnormally positioned expression domain). (c’’) fry-MO injected St.13 embryo (N = 3; n = 62; 87% and 96% with reduced and abnormally positioned expression domain, respectively).The distance between the blastopore and the prechordal mesoderm expressing gsc (dashed line) is reduced in the morphants. Dorsal views, anterior is oriented to the top. (d,e’’) Expression of chrd in the presumptive axial mesoderm. (d) Uninjected St. 10 embryo (N = 5; n = 95). (d’) St-MO injected St. 10 embryo (N = 2; n = 34; 6% with reduced expression domain) (d’’) fry-MO injected St. 10 embryo (N = 5; n = 113; 97% with reduced expression domain). Dorsal is oriented to the top. (e) Uninjected St.13 embryo (N = 4; n = 128). (e’) St-MO injected St.13 embryo (N = 2; n = 30, 10% with abnormally positioned expression domain) (e’’) fry-MO injected St.13 embryo (N = 4; n = 115, 92% and 95% with reduced and abnormally positioned expression domain, respectively). Dorsal views, anterior is oriented to the top. (f–h’’) Expression of pan-mesodermal marker brachyury (xbra). (f) Uninjected St. 10.5 embryo (N = 3; n = 47). (f’) St-MO injected St. 10.5 embryo (N = 2; n = 31). (f’’) fry-MO injected St. 10.5 embryo (N = 3; n = 53). (g) Uninjected St. 13 embryo (N = 2; n = 44). (g’) St-MO injected St. 13 embryo (N = 2; n = 28; 7% with abnormally positioned expression domain) (g’’) fry-MO injected St. 13 embryo (N = 2; n = 52; 98% with abnormally positioned expression domain). (h) Uninjected St. 15 embryo (N = 3; n = 48). (h’) St-MO injected St. 15 embryo (N = 2; n = 33). (h’’) fry-MO injected St. 15 embryo (N = 3; n = 45). Dorsal views, anterior is oriented to the top. (i–l’’) Expression of not in the chordamesoderm and anterior neuroectoderm. (i) Uninjected St. 10.5 embryo (N = 2; n = 52). (i’) St-MO injected St. 10.5 embryo (N = 2; n = 31). (i’’) fry-MO injected St. 10.5 embryo (N = 2; n = 47). (j) Uninjected St. 13 embryo (N = 3; n = 39). Dorsal is oriented to the top. (j’) St-MO injected St. 13 embryo (N = 2; n = 27; 4% abnormally positioned expression domain). (j’’) fry-MO injected St. 13 embryo (N = 3; n = 43; 100% with abnormally positioned expression domain). (k) Uninjected St. 13.5 embryo (N = 2; n = 29). (k’) St-MO injected St. 13.5 embryo (N = 2; n = 24). (k’’) fry-MO injected St. 13.5 embryo (N = 2; n = 32, 63% with abnormally positioned expression domain). (l) Uninjected St. 15 embryo (N = 3; n = 46). (l’) St-MO injected St. 15 embryo (N = 2; n = 28). (l’’) fry-MO injected St. 15 embryo (N = 3; n = 59). Dorsal views, anterior is oriented to the top. Note: not expression in the epiphysis (arrowheads) is initiated in fry-depleted embryos at the same time as controls, indicating the morphants are not developmentally delayed. Dashed lines indicate dorsal mesoderm elongation. The stage of injected embryos was established based on the stage of uninjected embryos from the same clutch. Representative embryos are shown. Embryos were injected into both dorsal blastomeres at the 4-cell stage with 15 ng of fry-MO or St-MO.
	Figure 3. Fry is required for normal blastopore closure. (a–h) Uninjected or fry-MO (15 ng) injected embryos were fixed at the indicated gastrulation stage for blastopore closure measurements. Representative embryos for each stage are shown. Gastrula stage embryos are oriented dorsal to the top and neurula stage embryos are oriented anterior to the top. (i) Left: Quantification of the blastopore closure measurements on fixed uninjected embryos, fry-MO (15 ng) injected embryos and fry-MO (15 ng) + FD + LZ mRNA (800 pg) co-injected embryos at the indicated gastrulation stage. Right: Image showing the blastopore area (blue) and the area of the vegetal hemisphere of the embryo (total area, yellow). The ratio of these two measurements is plotted. 0 = blastopore closed. N: number of independent experiments, n: number of embryos. The stage of injected embryos was established based on the stage of uninjected control embryos. Means and standard deviation are indicated. Each point represents a single fixed embryo. Statistical significance was evaluated using Kruskal–Wallis test and Dunn's multiple comparisons test (****,††††p < 0.0001). * represents the comparison to the uninjected group and † represents the comparison to the fry-MO injected group.
	Figure 4. Fry depletion affects the motion of superficial involuting marginal zone cells. (a) Xenopus 4-cell stage embryos were dorsally injected with H2B-eGFP mRNA with or without fry-MO (15 ng) and mounted for light-sheet fluorescence microscopy at the beginning of gastrulation (St. 10). Time lapse movies were recorded during gastrulation and individual cells were tracked while moving toward the dorsal blastopore lip (DBL) (e.g. nuclei in color. Circles and lines indicate nuclei position and trajectory, respectively). H2B-eGFP mRNA (N = 5; total number of tracked cells = 319); H2B-eGFP mRNA + fry-MO injected embryos (N = 5; total number of tracked cells = 332). N: number of independent experiments. Representative images from time-lapse movies at selected time-points (t) are shown. Scale bar: 100 μm. (b) Individual cell persistence measurements were calculated as the ratio between the linear distance traveled by the cell and the total length of its path. Each point represents a single cell. Statistical significance was evaluated using two-tailed Mann Whitney U-test. ****p < 0.0001 indicates statistically significant differences between groups. The mean and standard deviation are indicated. (c) Histogram representing the percentage of cells from control embryos (H2B-eGFP) for the different persistence intervals. (d) Histogram representing the percentage of cells from fry-MO + H2B-eGFP embryos for the different persistence intervals. Statistical significance was evaluated using Chi-square test. **p < 0.001 indicates statistically significant differences were found between groups. (e) Individual cell instantaneous velocity measurement. The mean and standard deviation are indicated. Each point represents a single cell. Statistical significance was evaluated using two-tailed Mann Whitney U-test. ****p < 0.0001 indicates statistically significant differences between groups. (f) Average distance from each cell nucleus to the nearest neighbors for all cells within a certain distance region from the blastopore lip (region size = 30 μm; overlapping region size = 5 μm). Distance to neighbors was quantified from the 150 min time point onward (St. 11.5) of the movies shown in a. Number of cells in each window was always larger than 100 cells. Data in the graph is presented as means with standard deviation. Statistical significance was evaluated using Kruskal–Wallis test and Dunn's multiple comparisons test. ****p < 0.0001 and **p < 0.01 indicate statistically significant differences between groups.
	Figure 5. The cleft of Brachet and fibronectin fibrillar matrix formation are affected in fry-depleted embryos. (a–c) Formation of the cleft of Brachet on the dorsal side was analyzed in hemisected early gastrula stage embryos (St. 10.5). (a) Uninjected embryo (N = 2, n = 26). (b) Standard Control morpholino (St-MO) (15 ng) injected embryo (N = 2; n = 13). (c) fry-MO (15 ng) injected embryo (N = 2; n = 25, in 92% of embryos, the cleft of Brachet is only present anteriorly). * indicates the position of the dorsal blastopore lip; ** indicates the ventral blastopore lip (morphological feature used as indication that embryos were developmentally synchronized at stage 10.5); blue arrowheads indicate the anterior (A) and posterior ends (P) of the cleft, BC: blastocoel; BCR: blastocoel roof. (a’–c’) Magnifications of the black-boxed area in panels a-c. Representative embryos are shown. (d,e) Hemisections of early gastrula stage embryos (St. 10.5) immunostained for fibronectin. (d) Uninjected embryo. (e) fry-MO (15 ng) injected embryo. Black arrowheads indicate fibronectin presence at the BCR. Blue arrowheads indicate the posterior end (P) of the cleft. (d’,e’) Magnifications of the black-boxed area in panels d and e. For fibronectin quantification, a rectangle 25 μm wide and 100 μm long was drawn at a distance of 300 μm from the dorsal blastopore lip (*) across the cleft of Brachet (red-boxed area). (f) Fibronectin abundance was quantified as fluorescence intensity across the 25 μm width of the red rectangle and normalized to the mean fluorescence (see Methods) in uninjected embryos (N = 2; n = 7) and fry-MO (15 ng) injected embryos (N = 2; n = 8). Data in the graph is presented as mean with standard error. Statistical significance was evaluated using two-tailed Mann Whitney U-test. **** p < 0.0001 indicates statistically significant differences between groups.
	Figure 6. Loss of Fry affects morphological polarity and orientation of dorsal mesoderm cells. (a,b) Dorsal marginal zone explants were prepared from Xenopus embryos at early gastrula stage (St. 10.5) and the vegetal alignment zone (VgAZ)5, which corresponds to the axial mesoderm, was imaged at late gastrula stage (St. 13) to assess dorsal mesoderm cell morphology. (a) mem-mScarlet mRNA injected embryo (N = 2, n = 7). (b) fry-MO (15 ng) + mem-mScarlet mRNA co-injected embryo (N = 2, n = 7). N: number of independent experiments, n: number of explants. Scale bar: 100 μm. Representative explants are shown. (c,d) Cell orientation was quantified as the angle of the cell’s major axis with respect to the mediolateral axis (ML). The circles in the rose diagram refer to the percentage of cells that exhibited polarity angles for each bin. Orientation angles were binned from 0° to 90° in bins of 11.25°. A: anterior, P: posterior, ML: mediolateral. (c) mem-mScarlet mRNA injected embryo (total number of cells analyzed = 147). (d) fry-MO + mem-mScarlet mRNA co-injected embryo (total number of cells analyzed = 151). Statistically significant differences were found between groups, Chi-square test (****p < 0.0001). (e) Polarity index measurements of dorsal mesoderm cells calculated as the ratio between cell major axis and minor axis. (f) Cellular area measurements of dorsal mesoderm cells. (e,f) mem-mScarlet mRNA injected embryos (total number of cells analyzed = 660); fry-MO + mem-mScarlet mRNA co-injected embryos (total number of cells analyzed = 632). Each point represents a single cell. Statistical significance was evaluated using two-tailed Mann Whitney U-test. **** p < 0.0001 indicates statistically significant differences between groups. Means and standard deviation are indicated.
	Figure 7. hNDR1-PIF partially rescues axis elongation in fry-depleted embryos. (a–e) 4-cell Xenopus embryos were injected into both dorsal blastomeres as indicated and fixed at St. 30. (a) Uninjected embryos. (b) fry-MO (15 ng) injected embryos. (c) fry-MO (15 ng) + hNDR1-wt mRNA (250 pg) co-injected embryos (d) fry-MO (15 ng) + hNDR1-PIF mRNA (250 pg) co-injected embryos. (e) fry-MO (15 ng) + hNDR1-kd mRNA (250 pg) co-injected embryos. Representative embryos are shown. (f) Quantitation of the percentage of embryos showing the different phenotypes: “Not affected”, “Shortened axis” or “Shortened axis & Head-less” phenotypes. Embryos were scored as “Shortened axis” when presented < 80% of the body length relative to the average length of control embryos. Data on graph is presented as mean. N: number of independent experiments, n: number of embryos. Statistical significance was evaluated using Chi-square test (****,††††p < 0.0001 and †††p < 0.001). * represents the comparison to the uninjected group and † represents the comparison to the fry-MO injected group.
	Figure 8. Loss of Fry impairs convergent extension movements and can be compensated by constitutively active hNDR1-PIF kinase. (a–g) Dorsal marginal zone explants were prepared from Xenopus embryos at early gastrula stage (St. 10.5) and culture until late neurula stage (St. 19) when the elongation of the explant was evaluated. (a) Uninjected embryos. (b) Standard Control morpholino (St-MO) (15 ng) injected embryos. (c) fry-MO (15 ng) injected embryos and (d) fry-MO (15 ng) + FD + LZ mRNA (800 pg) co-injected embryos. (e) fry-MO (15 ng) + hNDR1-wt mRNA (250 pg) co-injected embryos (f) fry-MO (15 ng) + hNDR1-PIF mRNA (250 pg) co-injected embryos and (g) fry-MO (15 ng) + hNDR1-kd mRNA (250 pg) co-injected embryos. Representative explants are shown. (h) Percentage of elongation of dorsal marginal zone explants from embryos treated as indicated. Elongation was calculated as the difference between the initial and final length of the explants (St. 10.5 vs. St. 19) relative to the mean of the uninjected group (considered 100% elongation, dotted line). Each point represents a single explant. N: number of independent experiments, n: number of explants. Statistical significance was evaluated using Kruskal–Wallis test and Dunn's multiple comparisons test (****,††††p < 0.0001 and **,††p < 0.01). * represents the comparison to the uninjected group and † represents the comparison to the fry-MO injected group.
	Supplementary Fig. S1. Fry expression and localization during gastrulation. (a-d) Fry expression in Xenopus embryos. (a) Mid blastula stage embryo (St. 8). Dotted lines indicate the orientation of the hemisection (lateral view, animal pole up). (a’) Mid blastula stage embryo (St. 8) hemisection. Animal (An) and vegetal (Veg) poles are indicated. (b) Early gastrula stage embryo (St. 10.5) (vegetal view, dorsal up). (c) Late gastrula stage embryo (St. 12.5) (dorsal view). (c) Neurula stage embryo (St. 15) (dorsal view). Dotted lines indicate the orientation of the histological preparations showed in (b’,c’,d’). vmz: ventral marginal zone, dmz: dorsal marginal zone, bc: blastocoel, dec: deep layer of the ectoderm, am: axial mesoderm, ar: archenteron, nc: notochord, pm: paraxial mesoderm, im: intermediate mesoderm * indicates the position of the dorsal blastopore lip. Representative embryos are shown (e) Fry-GFP localization in dorsal mesoderm cells. Dorsal marginal zone explants were prepared from early gastrula embryos (St. 10.5) coinjected into both dorsal blastomeres of the 4-cell stage embryos with fry-GFP and mem-mScarlet mRNAs. Scale bar: 100 μm. A representative explant is shown (N = 2; n = 7) N: number of independent experiments, n: number of explants analyzed.
	Supplementary Fig. S2. Differentiated axial structures are present in dorsally fry-depleted embryos. (a,b) Expression of chrd in stage 28 (St. 28) embryos by in situ hybridization. (a) Uninjected embryo (N = 2; n = 36). (b) fry-MO (15 ng) injected embryo (N = 2; n = 41). (c,d) Expression of myoD in the paraxial mesoderm of stage 28 (St. 28) embryos by in situ hybridization. (c) Uninjected embryo (N = 2; n = 40). (d) fry-MO (15 ng) injected embryo (N = 2; n = 43). (e,f) Notochord immunostaining with MZ15 antibody of stage 32 (St. 32) embryos. (e) Uninjected embryo (N = 2; n = 28). (f) fry-MO (15 ng) injected embryo (N = 2; n = 34). (g,h) Somitic muscle immunostaining with 12/101 antibody of stage 32 (St. 32) embryos. (g) Uninjected embryo (N = 2; n = 31). (h) fry-MO (15 ng) injected embryo (N = 2; n = 30). N: number of independent experiments, n: number of embryos. Embryos with representative expression or staining patterns are shown. All embryos analyzed showed positive staining. (a’-h’) Histological preparations (transverse sections) of embryos showed on a-h. nc: notochord; nt: neural tube; sm: somites. Note that both axial tissues are detected in fry morphant embryos, however they develop abnormally (e.g. reduced notochord diameter, discontinuous muscle staining).
	Supplementary Fig. S3. Chordamesoderm elongation requires Fry function. Embryos at different stages were subject to in situ hybridization for notochord homeobox, not. Dorsal midline tissues elongation was measure on uninjected embryos, fry-MO (15 ng) injected embryos and fry-MO (15 ng) + FD+LZ mRNA (800 pg) coinjected embryos at early gastrula stage (St. 10.5) and late gastrula stage (St. 13). Right: Scheme of the metrics used: ratio of not expression domain length (not length, white) over whole-embryo length (yellow). N: number of independent experiments, n: number of embryos. The stage of injected embryos was established based on the stage of uninjected littermates. Data in the graphs is presented as means with standard deviation. Each point represents a single embryo. Statistical significance was evaluated using Kruskal-Wallis test and Dunn's multiple comparisons test (****,†††† p<0.0001). * represents the comparison to the uninjected group and † represents the comparison to the fry-MO injected group.
	Supplementary Fig. S4. Blastopore formation and closure in fry-depleted embryos. Still frames from time-lapse movies (see Supplementary Movie S1) of gastrulating embryos at the indicated time-point (t) (vegetal view). Embryos were mounted at late blastula (St. 9) (t = 0). (a-d) Representative uninjected embryos (n = 12). (e-h) Representative fry-MO (15 ng) injected embryos (n = 12). Note that the blastopore formation is laterally expanded in fry-depleted representative embryos. Note all embryos present different degrees of blastopore closure delay. Only the embryo in h does not achieve blastopore closure. Dotted yellow arrows indicate the position and length of the dorsal blastopore lip when it is formed. D: dorsal; V: ventral.
	Supplementary Fig. S5. Fry depletion does not affect tissue separation behavior of dorsal mesoderm cells. (a,b) BCR assay for separation behavior in Xenopus embryos. Dorsal mesoderm test aggregates (yellow arrowheads) or deep layer of the ectoderm test aggregates (blue arrowheads) were prepared from uninjected (a) or fry-MO (15 ng) injected embryos (b) and placed on an uninjected explanted BCR. Representative aggregates are shown. Tissue separation behavior was evaluated at time (t) = 45 min (a’,b’). Test aggregates that remained on explanted BCR surface are indicated by arrowheads. Note that ectodermal aggregates sunk on the surface of the explanted BCR while dorsal mesoderm test aggregates remain on the surface. (c) Quantification of BCR assay: percentage of mesoderm aggregates that exhibited tissue separation behavior. Data in the graph is presented as means with standard deviation. N: number of independent experiments, n: number of mesoderm test aggregates. Statistical significance was evaluated using two-tailed Mann Whitney U-test. No statistically significant differences were found between groups (p = 0.4258).
	Supplementary Fig. S6. hNDR1-PIF rescues the chordamesoderm elongation in fry-depleted embryos. Neurula stage embryos (St. 15) were subject to in situ hybridization for notochord homeobox, not. Dorsal midline tissues elongation was measure as the length of not expression domain divided by the length of the whole-embryo of uninjected embryos, fry-MO (15 ng) injected embryos, fry-MO (15 ng) + hNDR1-wt mRNA (250 pg) coinjected embryos, fry-MO (15 ng) + hNDR1-PIF mRNA (250 pg) coinjected embryos, fry-MO (15 ng) + hNDR1-kd mRNA (250 pg) coinjected embryos. N: number of independent experiments, n: number of embryos. The stage of injected embryos was established based on the stage of uninjected littermates and confirmed by the presence of not expression in the anterior neuroectodermal domain. Data in the graphs is presented as means with standard deviation. Each point represents a single embryo. Statistical significance was evaluated using Kruskal-Wallis test and Dunn's multiple comparisons test (**** p<0.0001, †† p< 0.01). * represents the comparison to the uninjected group and † represents the comparison to the fry-MO injected group.
	Supplementary Fig. S7. Dorsal overexpression of hNDR1 functional variants result in mild axis elongation defects. (a-d) 4-cell stage Xenopus embryos were injected into both dorsal blastomeres as indicated and fixed at stage 30 (St. 30). (a) hNDR1-wt mRNA (250 pg) dorsally injected embryos. (b) hNDR1-PIF mRNA (250 pg) dorsally injected embryos. (c) hNDR1-kd mRNA (250 pg) dorsally injected embryos. Representative embryos are shown. (d) Quantitation of the percentage of dorsally injected embryos showing the different phenotypes: “Not affected”, “Shortened axis” or “Shortened axis & Head-less” phenotypes. Note that the axis phenotype is a mild axis elongation defect. Data on graph is presented as mean. N: number of independent experiments, n: number of embryos. Statistical significance was evaluated using Chi-square test. **** p<0.0001 indicates statistically significant differences relative to uninjected group. (e-g) 4-cell stage Xenopus embryos were injected into both ventral blastomeres as indicated and fixed at stage 30 (St. 30). (e) hNDR1-wt mRNA (250 pg) ventrally injected embryos (N = 2, n = 48). (f) hNDR1-PIF mRNA (250 pg) ventrally injected embryos (N = 2, n = 55). (g) hNDR1-kd mRNA (250 pg) ventrally injected embryos (N = 2, n = 36).
	Still from Supplementary Movie S1. Blastopore closure in uninjected and fry-depleted embryos. Time-lapse movies of gastrulating embryos. (left) Uninjected embryo (n = 12) (still frames a in Supplementary Fig. S5). (middle and right) fry-MO (15 ng) injected embryos (n = 12) (still frames e and f respectively in Supplementary Fig. S4). Note both embryos present blastopore closure delay relative to the uninjected embryo. Timestamp shows minutes elapsed. The movie begins at late blastula stage (St. 9) and continues through neurulation (St. 15). 1 frame every 3 minutes.
	Still from Supplementary Movie S2. Time-lapse movies of representative embryos subjected to light-sheet fluorescence microscopy. (left) H2B-eGFP mRNA injected embryo (control). (right) fry-MO (15 ng) and H2B-eGFP mRNA coinjected embryo. 1 frame every 3 minutes.

Bindels, mScarlet: a bright monomeric red fluorescent protein for cellular imaging. 2017, Pubmed

Bindels, mScarlet: a bright monomeric red fluorescent protein for cellular imaging. 2017, Pubmed
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