Lymphatic Defects in Zebrafish sox18 Mutants Are Exacerbated by Perturbed VEGFC Signaling, While Masked by Elevated sox7 Expression
<p>The <span class="html-italic">sox18<sup>sa12315</sup></span> mutant behaves as expected for a null allele. (<b>A</b>) On the left is a schematic representation of the Sox18 protein, with the HMG-box domain in blue. The G > A transition and the premature stop codon introduced in the <span class="html-italic">sa12315</span> mutant are indicated. Fragments of the electropherograms derived using Sanger sequencing of the region surrounding the mutation in wt (<span class="html-italic">sox18<sup>+/+</sup></span>), heterozygous (<span class="html-italic">sox18<sup>+/−</sup></span>) or homozygous mutants (<span class="html-italic">sox18<sup>−/−</sup></span>) are reported on the right. The restriction site for the BstNI/MvaI enzymes (boxed sequence) is disrupted by the mutation. (<b>B</b>) Embryos derived from <span class="html-italic">sa12315</span> heterozygote matings and injected with subcritical doses of <span class="html-italic">sox7</span>-MO were collected in several independent experiments and analyzed in vivo at 2 dpf and 3 dpf or fixed at around 30 hpf for ISH, as shown in (<b>C</b>). The histogram on the right shows the trunk–tail circulatory phenotypes observed at 3 dpf. In control embryos, i.e., uninjected or injected with a standard control MO (first and second bars, respectively), trunk–tail circulatory defects are present in a small percentage of embryos. On the contrary, the partial knockdown of <span class="html-italic">sox7</span> causes a blockage in trunk–tail circulation in a dose-dependent manner (third and fourth bars). Circulatory defects are genotype-dependent (see <a href="#app1-cells-12-02309" class="html-app">Table S1</a>). (<b>C</b>) ISHs were performed on embryos derived from <span class="html-italic">sa12315</span> heterozygote matings and injected with subcritical doses of <span class="html-italic">sox7</span>-MO, as shown in (<b>B</b>), fixed at around 30 hpf. Upper panels show control ISH performed with the endothelial marker <span class="html-italic">cdh5,</span> showing no gross alteration in embryos of the three different genotypes. Lower panels show ISHs performed with a probe for <span class="html-italic">vsg1/plvapb</span>, whose expression was particularly downregulated in double partial <span class="html-italic">sox7/sox18</span> morphants [<a href="#B29-cells-12-02309" class="html-bibr">29</a>]. Higher magnification images of the trunk–tail regions of the embryos are also shown. Experiments were repeated twice; all <span class="html-italic">plavpb</span> stained embryos and a subset of <span class="html-italic">cdh5</span> stained embryos were genotyped; numbers in each image refer to a single experiment. Lateral views, anterior to the left. Pictures were taken at 40× and 63× magnification, for lower and higher magnification images respectively.</p> "> Figure 2
<p>Homozygous <span class="html-italic">sox18</span> mutants show subtle but statistically significant defects in thoracic duct (TD) formation. (<b>A</b>) Confocal trunk images representing wt (+/+) and <span class="html-italic">sox18<sup>sa12315</sup></span> homozygous mutant larvae (−/−) in the <span class="html-italic">Tg(lyve1b:DsRed)</span> line at 5dpf. Large and small white arrowheads point to TD+ segments (of typical or thinner aspect, respectively) while asterisks indicate the absence of TD. (<b>B</b>) The graph reports the mean number of TD+ segments, counted along 10 consecutive trunk segments, together with the Standard Error of the Mean (SEM), in all analyzed embryos of the three genotypes (wt: <span class="html-italic">sox18</span><sup>+/+</sup>, het: <span class="html-italic">sox18</span><sup>+/−</sup>, hom: <span class="html-italic">sox18</span><sup>−/−</sup>). Data were gathered in three independent experiments, and each symbol represents the number of TD+ segments of a single analyzed larva. n = number of larvae, ** = <span class="html-italic">p</span> < 0.01. TD = thoracic duct; DA = dorsal aorta; PCV = posterior cardinal vein. Lateral view, anterior to the left.</p> "> Figure 3
<p>TD formation defects are exacerbated upon slight perturbation of Vegfc signaling. The progeny of <span class="html-italic">sox18<sup>sa12315</sup></span> heterozygote matings in the <span class="html-italic">Tg(fli1a:EGFP)<sup>y1</sup></span> line were injected with a subcritical dose of <span class="html-italic">vegfc</span>-MO or left uninjected; TD formation was analyzed at 5dpf. (<b>A</b>) Confocal trunk images of uninjected wt (+/+) and <span class="html-italic">sox18</span> homozygous mutant (−/−) larvae. Arrowheads point to TD+ segments, while asterisks indicate the absence of TD; a smaller arrowhead marks a thinner TD+ segment. (<b>B</b>) The graph reports the mean number of TD+ segments, counted along 10 consecutive trunk segments, together with the SEM, for all analyzed larvae of each genotype (wt: sox18<sup>+/+</sup>, het: sox18<sup>+/−</sup>, hom: sox18<sup>−/−</sup>). Each symbol represents the number of TD+ segments of a single larva; data were gathered in several independent experiments. Uninjected larvae on the left are compared to larvae with partially reduced Vegfc on the right. n = number of larvae, * = <span class="html-italic">p</span> < 0.05; ** = <span class="html-italic">p</span> < 0.01; *** = <span class="html-italic">p</span> < 0.001. TD = thoracic duct; DA = dorsal aorta; PCV = posterior cardinal vein. Lateral view, anterior to the left.</p> "> Figure 4
<p>The expression of <span class="html-italic">sox7</span> in the PCV is upregulated in <span class="html-italic">sox18</span> mutants, but not in <span class="html-italic">sox18</span> morphants. (<b>A</b>) Representative images of <span class="html-italic">sox7</span> ISH on embryos at around 26 hpf derived from matings of <span class="html-italic">sox18<sup>sa12315</sup></span> heterozygotes in the <span class="html-italic">Tg(lyve1b:DsRed)</span> line. Higher magnifications of the trunk region are shown below the full size images. Compared to wt embryos, the <span class="html-italic">sox7</span> ISH signal in the PCV is elevated in the great majority of <span class="html-italic">sox18</span><sup>−/−</sup> homozygotes and, to a lesser extent, in <span class="html-italic">sox18</span><sup>+/−</sup> heterozygotes. Numbers in each image state the number of embryos with the reported phenotype over the total analyzed embryos in one representative experiment. Lateral views, anterior to the left. Pictures were taken at 40× and 63× magnification, for lower and higher magnification images respectively. (<b>B</b>) Left, representative ImageJ-modified images, used to perform the quantification of the <span class="html-italic">sox7</span> ISH signal in the PCV and the DA (as described in Materials and Methods) on 26 hpf wt (+/+), <span class="html-italic">sox18<sup>sa12315</sup></span> heterozygotes (+/−) or homozygous mutants (−/−). The graph on the right shows the calculated PCV/DA ratio in each embryo; embryos are grouped based on their genotypes: mean values and SEM are indicated. (<b>C</b>) The same analysis was performed on <span class="html-italic">sox7</span> ISH of <span class="html-italic">sox18</span> morphants and control embryos, as shown in <a href="#app1-cells-12-02309" class="html-app">Figure S6</a>. The calculated PCV/DA ratio of each embryo is shown in the graph; mean values and SEM for std-MO injected embryos and <span class="html-italic">sox18</span> morphants are indicated. n = number of embryos, ** = <span class="html-italic">p</span> < 0.01; DA = dorsal aorta; PCV = posterior cardinal vein. The analysis was also repeated on ISHs of <span class="html-italic">sox18<sup>sa12315</sup></span> mutants in the <span class="html-italic">Tg(fli1a:EGFP)<sup>y1</sup></span> reporter line with similar results. ISH experiments on <span class="html-italic">sox18<sup>sa12315</sup></span> mutants were repeated at least three times. Data shown in A and B were generated on different clutches of embryos.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Zebrafish Lines and Maintenance
2.2. Genotyping
2.3. MO Microinjections
2.4. In Situ Hybridizations
2.5. Phenotypic Analyses
2.6. Statistical Analyses
3. Results
3.1. The sa12315 Mutation Is a Loss-of-Function Allele of sox18
3.2. sa12315 Mutants Show Mild Lymphatic Defects, Which Are Exacerbated by Perturbed VEGFC Signaling
3.3. sox18sa12315 Mutants Have Milder Lymphatic Phenotypes Than sox18 Morphants
3.4. Ectopic Expression of sox7 in the PCV of sox18sa12315 Mutants, but Not sox18 Morphants
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Moleri, S.; Mercurio, S.; Pezzotta, A.; D’Angelo, D.; Brix, A.; Plebani, A.; Lini, G.; Di Fuorti, M.; Beltrame, M. Lymphatic Defects in Zebrafish sox18 Mutants Are Exacerbated by Perturbed VEGFC Signaling, While Masked by Elevated sox7 Expression. Cells 2023, 12, 2309. https://doi.org/10.3390/cells12182309
Moleri S, Mercurio S, Pezzotta A, D’Angelo D, Brix A, Plebani A, Lini G, Di Fuorti M, Beltrame M. Lymphatic Defects in Zebrafish sox18 Mutants Are Exacerbated by Perturbed VEGFC Signaling, While Masked by Elevated sox7 Expression. Cells. 2023; 12(18):2309. https://doi.org/10.3390/cells12182309
Chicago/Turabian StyleMoleri, Silvia, Sara Mercurio, Alex Pezzotta, Donatella D’Angelo, Alessia Brix, Alice Plebani, Giulia Lini, Marialaura Di Fuorti, and Monica Beltrame. 2023. "Lymphatic Defects in Zebrafish sox18 Mutants Are Exacerbated by Perturbed VEGFC Signaling, While Masked by Elevated sox7 Expression" Cells 12, no. 18: 2309. https://doi.org/10.3390/cells12182309