XB-ART-55821
Dev Biol
2019 Jun 15;4502:115-131. doi: 10.1016/j.ydbio.2019.03.010.
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Desmoplakin is required for epidermal integrity and morphogenesis in the Xenopus laevis embryo.
Bharathan NK
,
Dickinson AJG
.
???displayArticle.abstract???
Desmoplakin (Dsp) is a unique and critical desmosomal protein, that is integral to epidermal development. However, it is unclear whether this protein is required specifically for epidermal morphogenesis. Using morpholinos or Crispr/Cas9 mutagenesis we decreased the function of Dsp in frog embryos to better understand its role during epidermal development. Dsp morphant and mutant embryos had developmental defects such as epidermal fragility that mimicked what has been reported in mammals. Most importantly, we also uncovered a novel function for Dsp in the morphogenesis of the epidermis in X. laevis. In particular, Dsp is required during the process of radial intercalation where basally located cells move into the outer epidermal layer. Once inserted these newly intercalated cells expand their apical surface and then they differentiate into specific epidermal cell types. Decreased levels of Dsp resulted in the failure of the radially intercalating cells to expand their apical surface, thereby reducing the number of differentiated multiciliated and secretory cells. Such defects correlate with changes in E-cadherin levels and actin and microtubule localization which could explain the defects in apical expansion. A mutated form of Dsp that maintains cell-cell adhesion but eliminates the connections to the cytoskeleton results in the same epidermal morphogenesis defect. These results suggest a specific role for Dsp in the apical expansion of cells during radial intercalation. We have developed a novel system, in the frog, to demonstrate for the first time that desmosomes not only protect against mechanical stress but are also critical for epidermal morphogenesis.
???displayArticle.pubmedLink??? 30935896
???displayArticle.pmcLink??? PMC6659752
???displayArticle.link??? Dev Biol
???displayArticle.grants??? [+]
Species referenced: Xenopus laevis
Genes referenced: cdh1 ctnnb1 dsp krt61 mcc tuba4b
GO keywords: epidermis morphogenesis [+]
???displayArticle.antibodies??? Cdh1 Ab1 Ctnnb1 Ab12 Krt5.2 Ab1 dsp Ab1 tuba4a Ab20
???displayArticle.morpholinos??? dsp MO1 dsp MO2
gRNAs referenced: dsp gRNA1 dsp gRNA2
???displayArticle.disOnts??? skin disease
Phenotypes: Xla Wt + Hsa.DSP{del} (Fig. 7 D) [+]
Xla Wt + Hsa.DSP{del}
(Fig. 7 F F')
Xla Wt + Hsa.DSP{del} (Fig. 7 H)
Xla Wt + dsp CRISPR (Fig. 2 H)
Xla Wt + dsp CRISPR (FIg. 2 M)
Xla Wt + dsp CRISPR (Fig. S 6 D D' D")
Xla Wt + dsp CRISPR2 (Fig. 2 I)
Xla Wt + dsp CRISPR2 (Fig. 2 N)
Xla Wt + dsp CRISPR2 (Fig. S 6 E E' E")
Xla Wt + dsp MO (Fig. 2 F)
Xla Wt + dsp MO (Fig. 2 F)
Xla Wt + dsp MO (Fig. 2 K)
Xla Wt + dsp MO (Fig. 2 L)
Xla Wt + dsp MO (Fig. 4 B)
Xla Wt + dsp MO (Fig. 4 D E)
Xla Wt + dsp MO (Fig. 4 G H)
Xla Wt + dsp MO (Fig. 4 K K')
Xla Wt + dsp MO (Fig. 4 L L')
Xla Wt + dsp MO (Fig. 4 N N' O)
Xla Wt + dsp MO (Fig. 5 F G H K L M)
Xla Wt + dsp MO (Fig. 6 B B' B")
Xla Wt + dsp MO (Fig. 6 D)
Xla Wt + dsp MO (Fig. 6 I I' I'')
Xla Wt + dsp MO (Fig. S 3 C D)
Xla Wt + dsp MO (Fig. S 4 C C' C")
Xla Wt + dsp MO (Fig. S 4 F F' F'')
Xla Wt + dsp MO (Fig. S 4 I I' I")
Xla Wt + dsp MO (Fig. S 5 D)
Xla Wt + dsp MO (Fig. S 6 B B' B")
Xla Wt + dsp MO
Xla Wt + dsp MO + Impact Assay (Fig. 3 C)
Xla Wt + dsp MO + Rotation Assay (Fig. 3 F)
Xla Wt + Hsa.DSP{del} (Fig. 7 H)
Xla Wt + dsp CRISPR (Fig. 2 H)
Xla Wt + dsp CRISPR (FIg. 2 M)
Xla Wt + dsp CRISPR (Fig. S 6 D D' D")
Xla Wt + dsp CRISPR2 (Fig. 2 I)
Xla Wt + dsp CRISPR2 (Fig. 2 N)
Xla Wt + dsp CRISPR2 (Fig. S 6 E E' E")
Xla Wt + dsp MO (Fig. 2 F)
Xla Wt + dsp MO (Fig. 2 F)
Xla Wt + dsp MO (Fig. 2 K)
Xla Wt + dsp MO (Fig. 2 L)
Xla Wt + dsp MO (Fig. 4 B)
Xla Wt + dsp MO (Fig. 4 D E)
Xla Wt + dsp MO (Fig. 4 G H)
Xla Wt + dsp MO (Fig. 4 K K')
Xla Wt + dsp MO (Fig. 4 L L')
Xla Wt + dsp MO (Fig. 4 N N' O)
Xla Wt + dsp MO (Fig. 5 F G H K L M)
Xla Wt + dsp MO (Fig. 6 B B' B")
Xla Wt + dsp MO (Fig. 6 D)
Xla Wt + dsp MO (Fig. 6 I I' I'')
Xla Wt + dsp MO (Fig. S 3 C D)
Xla Wt + dsp MO (Fig. S 4 C C' C")
Xla Wt + dsp MO (Fig. S 4 F F' F'')
Xla Wt + dsp MO (Fig. S 4 I I' I")
Xla Wt + dsp MO (Fig. S 5 D)
Xla Wt + dsp MO (Fig. S 6 B B' B")
Xla Wt + dsp MO
Xla Wt + dsp MO + Impact Assay (Fig. 3 C)
Xla Wt + dsp MO + Rotation Assay (Fig. 3 F)
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Fig. 1. Desmosomes and desmoplakin in the epidermis of X. laevis embryos. A) Schematic showing a transverse section of the X. laevis embryonic epidermis based on actual histological sections. B) TEM images where black arrows indicate desmosomes located between outer epidermal cells. Scale bar = 1.8 μm. Inset shows higher magnification of a desmosome. Scale bar = 135 nm. C-D‴) Immunofluorescence of Dsp and beta-catenin in the epidermis. Dapi labeling of the nuclei was used as a counter stain. C-C‴) st. 19–20, in H arrows indicate regions where there is a less Dsp labeling and arrowheads indicate where there is enrichment of Dsp labeling. The same cells are indicated in panel C′. Scale bar = 27 μm. D-D‴) High magnification of a cell that appears to be apically emerging with high levels of Dsp and lower beta-catenin. Scale bar = 6 μm. D-D‴) High magnification of a cell that appears to be beginning to intercalate and has low levels of Dsp. Scale bar = 6 μm. Abbreviations = MCC = multiciliated cell, SVs = secretory vesicles, mito = mitochondria, TJ = tight junction, oe = outer epidermis, ie = inner epidermis. |
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Fig. 2. Decreased function of Dsp in the embryo. (A) Schematic showing where the DspMO1 (red bar) is predicted to bind to dsp.L mRNA as well as the predicted spliced products in Dsp morphants and controls. Black arrow heads indicate the region of primer sequences used for RT-PCR analysis. RT-PCR of dsp showing there is an alternative splice product in the DspMO1 morphants. Immunofluorescence of desmoplakin (white) in DspMO1 and CMO morphants. (B) Schematic showing where the DspMO2 (red bar) is predicted to bind to dsp.L mRNA as well as the predicted spliced products in Dsp morphants and controls. Black arrow heads indicate the region of primer sequences used for RT-PCR analysis. RT-PCR of dsp showing there is an alternative splice product in the DspMO1 morphants. Immunofluorescence of desmoplakin (white) in DspMO2 and CMO morphants. (C) Schematic showing where the dspCrispr1 (red bars) is predicted to target the dsp.L and dsp.S genes. Black arrow heads indicate the region of primer sequences used for mutation analysis. Results of a T7 endonuclease assay are shown of dspCrispr mutants showing there is an alternative product indicative of mutation. Immunofluorescence of desmoplakin (white) in dspCrispr mutants and controls. (D) Schematic showing where the dspCrispr2 (red bars) is predicted to target the dsp.L and dsp.S genes. Black arrow heads indicate the region of primer sequences used for mutation analysis. Results of a T7 endonuclease assay are shown of dspCrispr mutants showing there is an alternative product indicative of mutation. Immunofluorescence of desmoplakin (white) in dspCrispr mutants and controls. E-I) Lateral view of control, Dsp morphants and mutant embryos at stage 28–30. Anterior is to the left. Arrows indicate regions where the epidermis is broken and arrowheads point to blister like structures. Scale bars = 450 μm. J-N) Later view of control, Dsp morphants and mutant embryos at stage 40–41. Anterior is to the left. Arrows indicate regions where the epidermis is broken and arrowheads point to blister like structures. Scale bars = 450 μm. O) Analysis of phenotypic frequency in i) DspMO1 morphants (D1), ii) DspMO2 morphants (D2), iii) dspCrispr1 mutants (Cr1), dspCrispr2 mutants (Cr2) compared to controls (C). Orange indicates percentage with the defect indicated at the top. Abbreviations: WT = wildtype uninjected sibling embryos, E = exon, IF = immunofluorescence. |
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Fig. 3. Decreased Dsp results in less mechanical resilience and is specific to the epidermis. A) Schematic of experimental design for the Dropping Assay. Bar graphs summarizing quantification of the proportion of CMO and DspMO1 morphants with a ruptured epidermis after undergoing the Dropping Assay.* = statistical significance using Chi-Squared test. B-C) Lateral views of a representative control and Dsp morphant at stage 28–30. Anterior is to the left. Arrow indicates regions where the epidermis is broken and arrowheads point to blister like structures. Scale bars = 450 μm. D) Schematic of experimental design for the Rotation Assay. Bar graphs summarizing quantification of the proportion of CMO and DspMO1 morphants with a ruptured epidermis after undergoing the Rotation Assay. * = statistical significance using Chi-Squared test. E-F) Lateral views of a representative control and Dsp morphant at stage 28–30. Anterior is to the left. Arrow indicates regions where the epidermis is broken and arrowheads point to blister like structures. Scale bars = 450 μm. G) Schematic of epidermal target injections. H-I‴) Representative lateral views of the posterior of embryos as in G showing the embryo under light (Light), fluorescence (Fluor. MO) to visualize the morpholino alone and merged (Merge). Scale bars = 450 μm. H-H′) Control MO (CMO) I-I′) DspMO1 morphants. |
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Fig. 4. Decreased Desmoplakin results in abnormal epidermal morphology, MCC and SSC development. A-B) Histological sections of the epidermis in control (A) and DspMO1 morphants (B). Yellow arrowheads indicate space underlying the epidermis. Scale bars = 45 μm. C-C′) Representative control trunk epidermis labeled with tubulin (C), phalloidin and tubulin (C′). Scale bars = 50 μm. D-D′) Representative DspMO1 trunk epidermis labeled with tubulin (D), phalloidin and tubulin (D′). Scale bars = 50 μm. E) Quantification of the percentage of tubulin positive cells in control compared to DspMO1 morphants. * = statistical significance. F-F′) Representative control trunk epidermis labeled with tubulin (F), phalloidin and tubulin (F′). 2X magnified region of C and C’. Scale bars = 11 μm. G-G′) Representative DspMO1 trunk epidermis labeled with tubulin (G), phalloidin and tubulin (G′). 2X magnified region of D and D’. Scale bar = 11 μm. H) Quantification of the surface area of tubulin positive cells in control compared to DspMO1 morphants. * = statistical significance. I-J′) Sections of two representative control trunk epidermis labeled with tubulin (I,J), phalloidin and tubulin (I′,J′). Scale bars = 22 μm. K-L′) Sections of two representative DspMO1 trunk epidermis labeled with tubulin (J), phalloidin and tubulin (G′). Scale bar = 22 μm. M-M′) Representative control trunk epidermis labeled with PNA (M), PNA and E-cadherin (M′). Scale bar = 50 μm. N-N′) Representative DspMO1 trunk epidermis labeled with PNA (N), PNA and E-cadherin (N). Scale bar = 50 μm. O) Quantification of the percentage of PNA positive cells in control compared to DspMO1 morphants. Blue line represents the mean. * = statistical significance. Abbreviations; PNA-peanut agglutinin, MCC = multiciliated cell, SSC = small secretory cell, OE = outer ectoderm, IE = inner ectoderm. |
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Fig. 5. Tracking the epidermis. A) Schematic of outer epidermis labeling experiment. B) Representative image of trunk epidermis labeled with biotin directly after labeling without a washout period. Scale bar = 40 μm. C-C′) Representative image of trunk epidermis double labeled with biotin (C) and tubulin (blue, C′) and merge (C′). Scale bar = 40 μm. D-E) Two representative images of trunk epidermis from a control embryos after labeling with biotin. Scale bars = 45 μm. F-G) Two representative images of trunk epidermis from a DspMO1 morphant embryos after labeling with biotin. Scale bars = 45 μm. H) Quantification of the percentage of unlabeled cells in DspMO1 morphants compared to controls. Red line represents the mean. * = statistical significance. I-J) Two representative images of trunk epidermis from a control embryos after labeling with biotin at higher magnification. Scale bars = 20 μm. K-L) Two representative images of trunk epidermis from a DspMO1 morphant embryos after labeling with biotin at high magnification. Scale bars = 20 μm. M) Quantification of the relative change in surface area of unlabeled cells in DspMO1 morphants compared to controls. Red line represents the mean. * = statistical significance. N-O) Histogram analysis of surface areas of unlabeled cells in control (N) and DspMO1 (O). The red line indicates the surface area of 200 μm2 for comparisons. |
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Fig. 6. A-B′) Representative control and DspMO1 morphant trunk epidermis labeled with keratin (A,B; green), beta-catenin (A′,B’; pink) and merge (A′,B′). Scale bars = 25 μm. Beta-catenin labeling (pink) was used to provide a marker of the cortical region of the cell. C,D) alpha-tubulin labeling of cells from control (C) and DspMO1 morphants (D). Scale bars = 25 μm. E,F) Phalloidin labeling of F-actin from control (C) and DspMo1 morphants (D). Scale bars = 25 μm. G) Schematic of the experimental design for H-I′. H-H′) Representative control trunk epidermis labeled with E-cadherin (J), showing the fluorescein labeled MO (H′) and merge (H′). Scale bar = 25 μm. K-K′) Representative control trunk epidermis labeled with E-cadherin (I), showing the Fluorescein labeled MO (I′) and merge (I′). Scale bar = 25 μm. Abbreviations = Ecad = E-cadherin. |
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Fig. 7. DP-NTP expression in X. laevis embryos. A) Schematic of the major domains of desmoplakin in wildtype (WT) and DP-NTP construct. B) Desmoplakin labeled with an antibody B′) DP-NTP-GFP expression B′) Merge of B and B’. C,D) Lateral views of representative control (C) and DP-NTP expressing embryos. E-E′) Trunk epidermis of a representative control embryo, labeled with tubulin (pink, E) and phalloidin (green) merged with tubulin (E′). F-F′) Trunk epidermis of a representative DP-NTP expressing embryo, labeled with tubulin (pink, F) and phalloidin (green) merged with tubulin (F′). G,H). Keratin localization in the trunk epidermis of a representative control (G) DP-NTP expressing embryo (H). Scale bars = 25 μm. |
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Fig. 8. Model of how decreased Dsp affects radial intercalation of the epidermis of Xenopus. Dsp (pink) connects with keratins (grey) and is increased during apical expansion. With reduced Dsp, the intercalating cell does not have properly localized keratins or apical accumulation of actin and the apical surface does not expand sufficiently. |
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Supplemental Figure 1: Characterizing desmosomes in the developing epidermis using TEM. A) TEM image of a desmosome with filaments attached and a tight junction visible, scale bar = 660nm. B) Low magnification TEM image showing outer and inner epidermal cells at st. 30-31, scale bar = 2.5µm. C) Low magnification TEM image showing outer and inner epidermal cells at st. 40-41. Scale bar= 2.5µm. Black arrows indicate desmosomes located between outer epidermal cells, arrowheads indicate desmosomes between outer and inner epidermal cells and white arrowheads indicate desmosomes between inner epidermal cells. |
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Supplemental Figure 2: Characterization of Dsp expression. A) RT-PCR of Dsp at embryonic stages as well positive controls in the adult skin and heart. RT+ = reverse transcriptase was added, RT- = reverse transcriptase was not added. Primer sequences available upon request. B-E''') Immunofluorescence of Dsp (green) in the epidermis from various embryonic stages. Dapi (blue) and beta-catenin (pink) labeling were used as a counter stain. F-F''') A 3D rendering of images as shown in E-E''' were created and then rotated 90 degrees. G-G''') st. 30 where only the inner epidermal layer of cells are shown. All scale bars = 40µm |
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Supplemental Figure 3: Decreased Desmoplakin results in changes in ultrastructure, keratin localization and E-cadherin levels. A-D) TEM images where black arrows indicate desmosomes located between outer epidermal cells. Arrowheads indicate a large space between cells with decreased desmosomes. Scale bars= 300nm. Gaps could be a sheering artifact of the processing due to the lack of integrity in the epidermis. On the other hand they could reflect a change in the extracellular space with the loss of desmosomes. |
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Supplemental Figure 4: DspMO1 targeted to the face, eye and fin causes developmental defects. All scale bars= 85µm. A) Schematic showing the blastomere injected with MO to target the face. B-B’’) Frontal view of the face of a representative embryo with control MO in the face. Shows an embryo with light microscope (B), fluorescent (B’) and merge (B’’). The embryonic mouth forms normally. C-C’’) Frontal view of the face of a representative embryo with DspMO1 in the face. Shows embryo with light microscope (C), fluorescent (C’) and merge (C’’). The embryonic mouth does not form (arrow). D) Schematic showing the blastomere injected with MO to target the eye. E-E’’) Lateral view of the head of a representative embryo with control MO in the eye. Shows an embryo with light microscope (E), fluorescent (E’) and merge (E’’). F-F’’) Lateral view of the head of a representative embryo with DspMO1 in the eye, shows embryo with light microscope (F), fluorescent (F') and merge (F''). The abnormal eye is indicated by an arrow. G) Schematic showing the blastomere injected with MO to target the dorsal fin. H-H'') Lateral view of the head of a representative embryo with control MO in the dorsal fin. Shows an embryo with light microscope (H), fluorescent (H') and merge (H''). I-I'') Lateral view of the head of a representative embryo with DspMO1 in the fin, shows embryo with light microscope (I), fluorescent (I') and merge (I''). The abnormal fin is indicated by an arrow. |
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Supplemental Figure 5: Decreased Dsp specifically in the trunk caused a reduction in tubulin positive cells. A) Schematic showing the blastomere injected with MO to target the trunk epidermis. B) Trunk epidermis of a representative embryo with CMO, labeled with tubulin (pink) and showing fluorescent tagged morpholino (green). C) Trunk epidermis of a representative embryo with DspMO1, labeled with tubulin (pink) and showing region lacking fluorescent tagged morpholino (green). Scale bar= D) Trunk epidermis of a representative embryo with DspMO1, labeled with tubulin (pink) and showing fluorescent tagged morpholino (green). |
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Supplemental Figure 6: Decreased Dsp results in cortical gaps in keratin localization. A-E’’) Immunofluorescence of keratin (green) in the epidermis of Dsp morphants and mutants. Beta-catenin (purple) labeling was used to provide a marker of the cortical region of the cell. Scale bars = 25µm. |
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