Fig 1.
Schematic illustration of epidermal morphogenesis.
Different layers are labeled in different colors.
Table 1.
Summary of observed phenotypes from wild type (WT), Ovol1-deficient (Ovol1-/-), Ovol2-deficient (Ovol2 SSKO), Ovol2-overexpression (Ovol2 BT), and Ovol1/Ovol2-deficient (Ovol DKO) mice.
Fig 2.
(A) A schematic diagram shows the roles of Ovol proteins in epidermal development and differentiation. Red dashed lines represent the potential regulation exerted by Ovol on components of the cell lineage model. (B) Immunofluorescence images showing a mild decrease in the size of the K14-positive compartment in Ovol2-overexpressing epidermis at E18.5. Scale bar represents 50 μm. (C) GSEA of microarray data from E17.5 embryos (2 biological replicates per genotype) with Normalized Enrichment Score (NES), p-value (P), and False Discovery Rate (FDR).
Table 2.
Results from simulations with Ovol regulation can recapitulate the epidermal phenotypes of all mutants.
The model details and parameter values are shown in S1 Text.
Fig 3.
Time course images of layer formation from Base Model (with cell lineage information but without spatial regulation) exhibit highly heterogeneous distribution of cells.
All the parameters used in the simulations are in Table A in S2 Text.
Table 3.
3D simulation results with Ovol down-regulation of v0 and p0 and up-regulation of d2 can recapitulate the epidermal phenotypes of all mutants, in cell number wise.
Mean and standard deviation of the cell number in 3D model is over an ensemble of 20 simulations. The model details and parameter values are shown in S2 Text.
Fig 4.
Basal cell asymmetric division and polarized cell adhesion together control robust basal-suprabasal boundary formation.
(A) A schematic lineage diagram shows the asymmetric cell division. (B) Time course images of layer formation from Asymmetric Division Model. Black dashed lines represent the basement membrane. All the parameters used in the simulations are in Table A in S2 Text.
Fig 5.
Comparison in Sharpness Index and Isolation Ratio demonstrate the quantitative proof of improved layer formation with asymmetric cell division and polarized cell adhesion.
(A,C) Sharpness Index for Base Model and Asymmetric Division Model. Bar length represents the value of Sharpness Index at various height in the unit of cell numbers. Red, green and blue stack bars represent the portion of basal, spinous and granular cells at each slice. (B,D) Isolation Ratio for Base Model and Asymmetric Division Model. Mean and standard deviation in 3D model are over an ensemble of 20 simulations. All the parameters used in the simulations are in Table A in S2 Text.
Fig 6.
Selective cell adhesion significantly sharpens the boundaries between spinous and granular layers.
(A) A schematic diagram shows the selective cell adhesion mechanism. (B) Time course images of layer formation of Selective Adhesion Model. Black dashed lines represent the basement membrane. (C) Sharpness Index. Bar length represents the value of sharpness index at height in the unit of cell numbers. Red, green and blue stack bars represent the portion of basal, spinous and granular cells at height in the unit of cell numbers. (D) Isolation Ratio. Mean and standard deviation in 3D model is over an ensemble of 20 simulations. All the parameters used in the simulations are in Table A in S2 Text.
Fig 7.
Effectiveness of selective cell adhesion based on varied adhesion strength Fa and Fb.
The optimal results shows the selective cell adhesion works most efficiently when ratio Fa/Fb is between 2 and 6 (Pattern vi). All the parameters used in the simulations are in Table A in S2 Text.
Fig 8.
Effectiveness of selective cell adhesion based on various cell number and layer thickness.
The mechanism performs most efficiently when the cell layer thickness is around or below 4 cell diameter thick. All the parameters used in the simulations are in Table A in S2 Text.
Fig 9.
Long-range signaling or morphogen regulation enhances the stratification between spinous and granular cells.
(A) A schematic diagram shows the calcium regulation on Ovol. (B) Time course images of layer formation. Black dashed lines represent the basement membrane. (C) Sharpness Index for Signal Model. Bar length represents the value of sharpness index at height in the unit of cell numbers. Red, green and blue stack bars represent the portion of basal stem, spinous and granular cells at height in the unit of cell numbers. (D) Isolation Ratio. Mean and standard deviation in 3D model is over an ensemble of 20 simulations. All the parameters used in the simulations are in Table A in S2 Text.
Fig 10.
Comparison of cell number for the models.
In the Signal Model, negative regulation of basal cell proliferation and positive regulation of spinous cell differentiation into granular cells by the morphogen signaling is able to slow down the cell number’s growth rate and achieve steady state. All the parameters used in the simulations are in Table A in S2 Text.
Fig 11.
Flowchart of event coordination in the multiscale modeling approach.