Sonam S , Srnak JA , Perry KJ , Henry JJ .

R01 EY023979 NEI NIH HHS

             stem cell development

	Fig. 1. Larvae (stage 50–52) and adult (stage 66) Xenopus eyes. (A) Tadpole eye showing regions of the cornea. Region enclosed by white dotted line represents the central cornea (cc), green dotted line represents the region enclosing the peripheral cornea (pc), and the pigmented skin epithelium (sk) lies outside this line. (B) Schematic drawing of the larval Xenopus eye. The corneal epithelium is shaded light yellow, while the skin is shaded light grey. (C) Hoechst labeling in a larval corneal whole-mount. (D) Adult Xenopus eye. White dotted line encloses the central cornea (cc), green dotted line encloses the limbal region (lm), and yellow arrowhead points to the ventral eyelid (ve). The pigmented skin (sk) surrounds the eye. (E) Schematic drawing of the adult frog eye. The corneal epithelium is shaded light yellow, while the eyelid and skin is shaded light grey. (F) Hoechst labeling in a cross-section of adult Xenopus cornea. (a) apical surface of corneal epithelium, (b) basal surface of corneal epithelium, (ce) corneal epithelium, (de) dorsal eyelid, (en) corneal endothelium, (i) inner portion of eyelid, (ln) lens, (o) outer surface of eyelid, (on) optic nerve, (rt) retina, (st) corneal stalk, (sr) stroma, (vc) vitreous chamber. Scale bar in F equals 470 μm for A, 520 μm for C, 800 μm for D, and 400 μm for F. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 2. Confocal and fluorescence light microscopic images showing p63 antibody staining in X. laevis epithelial tissues. (A–D) Larval cornea whole-mounts showing p63 expression (green) is restricted to all basal cells (nuclei) of the central and peripheral cornea, as labeled. (A′-D′) Merged images for A-D with Hoechst labeled nuclei (magenta). (A-A′) Apical cells of central cornea exhibit no p63 expression. (B-B′) Localized p63 labeling is seen in all nuclei of the basal epithelium. (C-C′) p63 is not expressed in apical cells of peripheral corneal epithelium. (D-D′) All nuclei of basal cells in the peripheral cornea have uniform expression for p63. (E–H) Localization of p63 (green) in cryosections of adult cornea, eyelid and skin. The apical surface is located towards the top of each image, and the basal surface towards the bottom. (E′-H′) Merged images for E-H with Hoechst labeled nuclei (magenta). (E-E′) p63 labeling is detected in nuclei of basal and intermediate cells of the central cornea, but not in the nuclei of apical cells. The nuclei in the basal epithelium have relatively higher levels of p63 staining than those in the intermediate layer. (F-F′) In the limbal region, p63 label is primarily detected in nuclei of basal epithelial cells along with moderate expression in intermediate layer cells. (G-G′) Ventral eyelid showing p63 staining is localized to the nuclei of cells present mainly in the outer surface of the eyelid, with the cells in basal layer showing higher staining intensity. Some weak expression maybe seen in scattered basal cells within the inner surface of the eyelid. (H-H′) p63 expression is also detected in the surrounding skin epithelium, with nuclei in the basal layer showing higher expression compared to those of the intermediate layer cells. No staining is detected in cells of the outermost, apical layer of the skin. ive, inner ventral eyelid; ove, outer ventral eyelid. Scale bar in H′ equals 25 μm for A-D, A′-D′, and 50 μm for E-H, E′-H’. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 3. Confocal and fluorescence light microscopic images showing immunofluorescent staining for Paired box protein 6 (Pax6) in larval and adult frog epithelia. (A–D) Pax6 (green) localizes to the basal epithelial cells of central and peripheral cornea in the tadpoles, as labeled. (A′-D′) Merged images for A-D with Hoechst labeled nuclei (magenta). (A-A′) Pax6 expression is undetectable in apical cells of the central cornea. (B-B′) Both the nucleus and cytoplasm of basal cells in the central corneal epithelium show uniform Pax6 staining. However, expression is excluded from the peri-nuclear region in these cells. Pax6-positive cells have a tight packing arrangement. (C-C′) Pax6 is not expressed in the apical cells of peripheral corneal epithelium. (D-D′) Basal cells in the peripheral cornea also express Pax6. Fewer Pax6-positive cells were detected in the peripheral region. (E–H) Cross-sections of adult frog cornea, eyelid and skin stained with Pax6 (green) antibody, as labeled. The apical surface is located towards the top of each image and the basal surface towards the bottom. (E′-H′) Merged images for E-H with Hoechst labeled nuclei (magenta). (E-E′) Pax6 staining is not observed in the central cornea. (F-F′) Pax6 expression is also undetected in the limbal region. (G-G′) Pax6 staining is noted only in apical cells of the outer surface of the ventral eyelid, where expression is primarily localized to the cytoplasm of these cells. (H-H′) A similar pattern of Pax6 expression is seen in apical cells in the skin epithelium, outside the cornea. ive, inner ventral eyelid; ove, outer ventral eyelid. Scale bar in H′ equals 25 μm for A-D, A′-D′, and 50 μm for E-H, E′-H’. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 4. Antibody localization for Transcription factor 7 like 2 (Tcf7l2). Representative images from confocal and fluorescence light microscopy for larval and post-metamorphic frog corneas, as labeled. (A) Whole mount of larval Xenopus cornea showing presence of Tcf7l2 (green) labeled cells in the skin epithelium, surrounding the cornea. Tcf7l2-positive cells are rarely seen in the peripheral cornea. Regions labeled are those shown in B-G and B′-G’. (B–G) Higher magnification confocal images showing the distribution of Tcf7l2 (green) labeled cells in skin and cornea of larval animals, as labeled. (B′-G′) Merged images for B-G with Hoechst labeled nuclei (magenta). (B-B′) Apical cells of the skin epithelium exhibit Tcf7l2 antibody labeling. Tcf7l2 has cytoplasmic expression in a majority of these apical epithelial cells. (C-C′) Skin basal cells do not express Tcf7l2. (D-D′) No expression is observed in the apical cells of the central cornea. (E-E′) Basal cells in the central corneal epithelium also do not show presence of Tcf7l2. (F-F′) The apical epithelium of the peripheral cornea is predominantly devoid of Tcf7l2-positive cells. Tcf7l2 expressing cells (shown by white arrowhead) are rarely detected in the apical layer of the peripheral cornea. (G-G′) Basal epithelial cells of the peripheral cornea are devoid of antibody labeling. (H–K) Immunofluorescent staining for Tcf7l2 (green) on frozen sections of adult frog epithelia, as labeled. The apical surface is located towards the top of each image, and the basal surface towards the bottom. (H′-K′) Merged images for H-K with Hoechst labeled nuclei (magenta). (H-H′) Tcf7l2 staining is not present in the epithelial cell layers of the central cornea. (I-I′) No Tcf7l2 expression is detected in cells of the limbal epithelium. (J-J′) Cells in the basal and intermediate layers of the outer surface of the ventral eyelid show Tcf7l2 staining, with no expression noted in apical cells. The inner surface epithelium of the eyelid is negative for this protein. (K-K′) Tcf7l2 expression is observed in the basal and intermediate cells of the surrounding skin epithelium. Superficial cells of skin epithelium do not label with this antibody. cc, central cornea; ive, inner ventral eyelid; ove, outer ventral eyelid; pc, peripheral cornea; sk, skin. Scale bar in K′ equals 200 μm for A, 25 μm for B-G, B′-G′, and 50 μm for H-K, H′-K’. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 5. Confocal and fluorescence light microscopic images showing cellular localization of Keratin 19 (Krt19) in larval and post-metamorphic frog epithelia. (A–D) Antibody labeling in whole corneas showing the distribution and appearance of Krt19 (green) labeled cells in larval stages, as labeled. (A′-D′) Merged images for A-D with Hoechst labeled nuclei (magenta). (A-A′) Apical cells of the central corneal epithelium exhibit very faint Krt19 labeling. (B-B′) Krt19 is primarily localized in the cytoplasm of cells in the basal epithelium of the central cornea. Krt19 labeling looks uniform throughout the basal layer. (C-C′) Apical epithelium of the peripheral cornea with very weak staining for Krt19. (D-D′) Localized Krt19 labeling in the cytoplasm of all cells in the basal epithelium of the peripheral cornea. (E–H) Krt19 (green) immunostaining in mature Xenopus cornea, eyelid and skin, as labeled. The apical surface is located towards the top of each image and the basal surface towards the bottom. (E′-H′) Merged images for E-H with Hoechst labeled nuclei (magenta). (E-E′) Krt19 is detected in all the epithelial layers of the central cornea. Krt19 predominantly localizes to the apical epithelial cells, where it forms a layer on the surface of the corneal epithelium (indicated by white arrowheads in E and E′). (F-F′) Krt19 localization is observed in all epithelial layers of the limbal area. (G-G′) Ventral eyelid showing Krt19 labeling. Inner surface of the eyelid has Krt19-positive cells in all the layers. The staining is restricted to cells in the basal layer of the outer surface of the eyelid. (H-H′) Skin epithelium showing Krt19 staining. The labeled cells are largely localized to the basal layer, with few positive cells found in the intermediate layers. The outermost layer of skin does not express Krt19. ive, inner ventral eyelid; ove, outer ventral eyelid. Scale bar in H′ equals 25 μm for A-D, A′-D′, and 50 μm for E-H, E′-H’. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 6. Immunolocalization of vimentin in larval and adult frog epithelia and deeper tissues. (A–F) Confocal images showing presence of vimentin (green) expressing cells, which are the keratocytes found below the basal layer of the larval corneal epithelium. (A′-F′) Merged images for A-F with Hoechst labeled nuclei (magenta). (A-A′) No vimentin-positive cells were observed in the apical layer of the central cornea. (B-B′) Basal cells in the central cornea also do not express vimentin. (C-C′) In the central cornea region, vimentin expression is found in keratocytes, which have a dendritic morphology. (D-D′) Apical cells of the peripheral cornea do not show stain with vimentin antibody. (E-E′) No vimentin localization is detected in basal epithelial cells of the peripheral cornea of larvae. (F-F′) Keratocytes of the peripheral cornea also express vimentin. (G–J) Fluorescence light microscopic images showing vimentin (green) labeling in cross-sections of adult Xenopus epithelia, as labeled. The apical surface is located towards the top of each image, and the basal surface towards the bottom. (G′-J′) Merged images for G-J with Hoechst labeled nuclei (magenta). (G-G′) Vimentin expression is detected in the keratocytes that are present in the stromal layer. No staining is noted in central corneal epithelium. (H-H′) Vimentin-positive cells are also present in the stroma underlying the limbal epithelium. (I-I′) The eyelid has vimentin labeled cells in the dermis beneath the epithelial layer. (J-J′) Skin epithelium has moderate expression of vimentin, only in the basal cells. The antibody also labels a much higher number of cells in the dermal layer of the skin. ive, inner ventral eyelid; ove, outer ventral eyelid. Scale bar in J′ equals 25 μm for A-F, A′-F′, and 50 μm for G-J, G′-J’. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 7. Immunolabeling of larval and adult Xenopus epithelia with β1-integrin (β1-itg). (A–D) Confocal images showing that expression of β1-itg (green) is restricted to basal epithelial cells of the tadpole cornea. (A′-D′) Merged images for A-D with Hoechst labeled nuclei (magenta). (A-A′) Apical epithelial cells of the central cornea with no β1-itg label detected. (B-B′) β1-itg staining is predominantly membranous in the basal epithelial cells of the central cornea. Weak cytoplasmic expression is also observed in these cells. (C-C′) β1-itg staining is undetectable in the apical cells of the peripheral cornea. (D-D′) β1-itg stained basal epithelial cells in the peripheral cornea. (E–H) Fluorescence light microscopic images displaying β1-itg (green) antibody labeling on cryosections of adult Xenopus tissues, as labeled. The apical surface is located towards the top of each image, and the basal surface towards the bottom. (H′-K′) Merged images for H-K with Hoechst labeled nuclei (magenta). (E-E′) β1-itg is expressed throughout the entire thickness of the central corneal epithelium. A gradient in expression is observed, with the basal epithelial cells showing the highest expression. (F-F′) Limbal epithelial cells express β1-itg, with the maximum expression present in the basal layer. Moderate expression of β1-itg is seen in stromal cells underneath the corneal epithelium. (G-G′) Ventral eyelid showing β1-itg immunoreactivity. Basal cells in the outer surface of the ventral eyelid have higher expression of β1-itg. (H-H′) Epithelial cells in the skin display β1-itg labeling, with basal cells having the highest expression. ive, inner ventral eyelid; ove, outer ventral eyelid. Scale bar in H′ equals 25 μm for A-D, A′-D′, and 50 μm for E-H, E′-H’. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 8. Larval and adult Xenopus epithelia stained with E-cadherin (E-cad) antibody. (A–D) Confocal images showing uniform distribution of E-cad (green) in the membranes of epithelial cells in a larval Xenopus cornea. (A′-D′) Merged images for A-D with Hoechst labeled nuclei (magenta). (A-A′) E-cad localizes to the membranes in apical cells of the central corneal epithelium. (B-B′) Basal cells of the central corneal epithelium show E-cad expression predominantly associated with the membranes. Weak E-cad expression is also detected in the cytoplasm of the basal cells. (C-C′) Membrane bound E-Cad in apical cells of the peripheral corneal epithelium. (D-D′) E-cad labeling is associated with the membranes of basal epithelial cells of the peripheral cornea. (E–H) Fluorescence light microscopic images showing E-cad (green) staining on frozen sections of adult Xenopus epithelia, as labeled. The apical surface is located towards the top of each image, and the basal surface towards the bottom. (H′-K′) Merged images for H-K with Hoechst labeled nuclei (magenta). (E-E′) Epithelial cells throughout the entire thickness of the central cornea have uniform expression of E-cad in the membrane. (F-F′) E-cad localizes to the membrane of all epithelial cells in the limbal region. (G-G′) E-cad uniformly labels the membranes of epithelial cells in the inner and outer surface of the ventral eyelid. (H-H′) Cross-section of skin epithelium with E-cad membrane associated staining in the basal, intermediate and superficial layers. ive, inner ventral eyelid; ove, outer ventral eyelid. Scale bar in H′ equals 25 μm for A-D, A′-D′, and 50 μm for E-H, E′-H’. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 9. Immunofluorescent localization of β-catenin (β-cat) in larval and adult Xenopus epithelia. (A–D) Confocal images showing restricted localization of β-cat (green) in apical epithelial cells of the larval cornea. (A′-D′) Merged images for A-D with Hoechst labeled nuclei (magenta). (A-A′) β-catenin is associated with the membranes of epithelial cells found in the apical layer of the central cornea. (B-B′) No label is detected in the basal epithelial cells of the central cornea. (C-C′) Apical epithelial cells in the peripheral cornea have membrane-bound expression of β-catenin. (D-D′) Basal epithelial cells show no immunoreactivity with the β-catenin antibody. (E–H) Fluorescence light microscopic images display β-catenin (green) localization in cross-sections of adult frog epithelial tissues, as labeled. The apical surface is located towards the top of each image, and the basal surface towards the bottom. (H′-K′) Merged images for H-K with Hoechst labeled nuclei (magenta). (E-E′) β-catenin is widely expressed throughout the full thickness of the central cornea. Staining is also found in the corneal endothelium (en) and is denoted by white arrowheads in E and E’. (F-F′) Epithelial cells in the limbal region also show positive reactivity to the β-catenin antibody. (G-G′) Epithelial cells lining the inner and outer portion of ventral eyelid uniformly express β-catenin. (H-H′) Skin epithelial cells in all layers have membranous β-catenin expression, similar to that found in the cornea. en, corneal endothelium; ive, inner ventral eyelid; ove, outer ventral eyelid. Scale bar in H′ equals 25 μm for A-D, A′-D′, and 50 μm for E-H, E′-H’. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 10. Cellular localization of the transmembrane receptor, p75 in frog epithelial tissues. Confocal and fluorescence light microscopic images show p75 (green) labeling in larval and mature frog corneas. (A) Representative region of a larval whole-mount cornea showing a few scattered p75 more brightly labeled cells in the peripheral cornea (pc), and a higher number of p75 brightly labeled cells distributed in the skin (sk) outside of the cornea. No p75 brightly labeled cells were observed in the central cornea (cc). Higher magnification confocal images of these regions are shown in B-G. (B–G) Distribution of p75 (green) labeled cells in the skin and the cornea of larval animals. (B′-G′) Merged images for B-G with Hoechst labeled nuclei (magenta). (B-B′) The apical epithelium of the skin has cytoplasmic localization of p75 in a higher number of cells (marked by white arrowheads). (C-C′) Moderate expression of p75 is detected in the peri-nuclear region of basal skin epithelial cells. (D-D′) p75 expression is undetectable in the apical epithelium of the central cornea. (E-E′) Basal cells of the central cornea have peri-nuclear expression of p75. (F-F′) High p75 expression is noted in a few apical epithelial cells of the peripheral cornea (marked by white arrowheads). (G-G′) Basal cells in the peripheral cornea have faint expression of p75 in the peri-nuclear region. (H–K) Immunofluorescent staining for p75 (green) on frozen sections of the adult frog epithelial tissues, as labeled. The apical surface is located towards the top of each image, and the basal surface towards the bottom. (H′-K′) Merged images for H-K with Hoechst labeled nuclei (magenta). (H-H′) p75 is expressed throughout the full thickness of the central corneal epithelium. The localization is membranous, as well as cytoplasmic. (I-I′) Epithelial cells present in all the layers of the limbal region have p75 staining. (J-J′) Ventral eyelid showing p75 localization. The epithelia of both inner and outer surfaces of the ventral eyelid have p75 expression. A few cells more brightly labeled with p75 are also detected (marked by white arrowheads). (K-K′) The skin epithelium has p75 expression in all the cellular layers. cc, central cornea; ive, inner ventral eyelid; ove, outer ventral eyelid; pc, peripheral cornea; sk, skin. Scale bar in K′ equals 60 μm in A, 25 μm for B-G, B′-G′, and 50 μm for H-K, H′-K’. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 11. Larval and adult frog epithelia immunostained with Pax6 and Tcf7l2 antibodies. (A–C) Lower magnification confocal images of larval whole-mount cornea showing Pax6 (red), and Tcf7l2 (green) co-staining. The white dotted line represents the boundary demarcating the cornea and skin. (A) A gradient of Pax6 expression is higher in the central cornea (cc), and is lost progressively towards the peripheral cornea (pc), and skin (sk). (B) Tcf7l2-positive cells are abundant in the skin region. (C) Merged image showing Pax6 and Tcf7l2 expression. (D-G, D′-G′ and D”-G′) Cross-sections of adult frog cornea, eyelid and skin immunolabeled with Pax6 (red) and Tcf7l2 (green). The apical surface is located towards the top of each image, and the basal surface towards the bottom. D′, E′, F′ and G′ are merged images for D, D’; E, E’; F, F′ and G, G′, respectively, with Hoechst labeled nuclei (blue). (D, D′ and D′) No Pax6 or Tcf7l2 expression is detected in the central cornea. (E, E′, and E′) The limbal region has undetectable Pax6 or Tcf7l2. (F, F′ and F′) Ventral eyelid region showing Pax6 and Tcf7l2 expression. The inner surface of the eyelid does not stain for either antibody. Outer surface of the eyelid has Pax6 in the apical cells, and Tcf7l2 mainly in the basal layer of cells. (G, G′ and G′) Skin of the adult frog has Pax6 in apical cells of the epithelium, and Tcf7l2 in the basal and intermediate layers of cells. cc, central cornea; ive, inner ventral eyelid; ove, outer ventral eyelid; pc, peripheral cornea; sk, skin. Scale bar in G′ equals 60 μm for A-C, 50 μm for D-G, D′-G′, D′-G”. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 12. Summary of protein localization detected in the epithelial tissues of larval and adult Xenopus, as indicated. Relative expression levels are represented as undetectable, weak, moderate and high, as shown in the key. ‘#’ denotes few positive cells; ‘a’ denotes expression only in the apical layer; ‘b’ denotes expression only in the basal layer; ‘g’ denotes gradient in expression.

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