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alpha3beta1 Integrin is required for normal development of the epidermal basement membrane.

DiPersio CM, Hodivala-Dilke KM, Jaenisch R, Kreidberg JA, Hynes RO - J. Cell Biol. (1997)

Bottom Line: Laminin-5 and other matrix proteins remained associated with both the dermal and epidermal sides of blisters, suggesting rupture of the basement membrane itself, rather than detachment of the epidermis from the basement membrane as occurs in some blistering disorders such as epidermolysis bullosa.Consistent with this notion, primary keratinocytes from alpha3beta1-deficient skin adhered to laminin-5 through alpha6 integrins.However, alpha3beta1-deficient keratinocytes spread poorly compared with wild-type cells on laminin-5, demonstrating a postattachment requirement for alpha3beta1 and indicating distinct roles for alpha3beta1 and alpha6beta4.

View Article: PubMed Central - PubMed

Affiliation: Center for Cancer Research, and Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA.

ABSTRACT
Integrins alpha3beta1 and alpha6beta4 are abundant receptors on keratinocytes for laminin-5, a major component of the basement membrane between the epidermis and the dermis in skin. These integrins are recruited to distinct adhesion structures within keratinocytes; alpha6beta4 is present in hemidesmosomes, while alpha3beta1 is recruited into focal contacts in cultured cells. To determine whether differences in localization reflect distinct functions of these integrins in the epidermis, we studied skin development in alpha3beta1-deficient mice. Examination of extracellular matrix by immunofluorescence microscopy and electron microscopy revealed regions of disorganized basement membrane in alpha3beta1-deficient skin. Disorganized matrix was first detected by day 15.5 of embryonic development and became progressively more extensive as development proceeded. In neonatal skin, matrix disorganization was frequently accompanied by blistering at the dermal-epidermal junction. Laminin-5 and other matrix proteins remained associated with both the dermal and epidermal sides of blisters, suggesting rupture of the basement membrane itself, rather than detachment of the epidermis from the basement membrane as occurs in some blistering disorders such as epidermolysis bullosa. Consistent with this notion, primary keratinocytes from alpha3beta1-deficient skin adhered to laminin-5 through alpha6 integrins. However, alpha3beta1-deficient keratinocytes spread poorly compared with wild-type cells on laminin-5, demonstrating a postattachment requirement for alpha3beta1 and indicating distinct roles for alpha3beta1 and alpha6beta4. Our findings support a novel role for alpha3beta1 in establishment and/or maintenance of basement membrane integrity, while alpha6beta4 is required for stable adhesion of the epidermis to the basement membrane through hemidesmosomes.

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Distributions of entactin  and type VII collagen in the developing skin. Frozen sections from  mouse embryonic skin at days E11.5  (A and B), E15.5 (C and D), or  E17.5 (E and F) of development  were stained with antisera against  entactin (A, C, and E) or type VII  collagen (B, D, and F). Staining patterns for entactin or type VII collagen were identical in wild-type (A,  C, and D) and heterozygous (E and  F) embryos; type VII collagen staining in B is from an α3-, E11.5  embryo, but was identical to that of  a wild-type embryo at this stage. e,  epidermis; d, dermis. Bar, 50 μm.
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Figure 6: Distributions of entactin and type VII collagen in the developing skin. Frozen sections from mouse embryonic skin at days E11.5 (A and B), E15.5 (C and D), or E17.5 (E and F) of development were stained with antisera against entactin (A, C, and E) or type VII collagen (B, D, and F). Staining patterns for entactin or type VII collagen were identical in wild-type (A, C, and D) and heterozygous (E and F) embryos; type VII collagen staining in B is from an α3-, E11.5 embryo, but was identical to that of a wild-type embryo at this stage. e, epidermis; d, dermis. Bar, 50 μm.

Mentions: The developmental expression and general distributions of several ECM proteins were identical in skin from wildtype, heterozygous, and α3- embryos at each developmental stage examined; therefore, panels in Fig. 6 show representative data for entactin and type VII collagen. Entactin clearly defined a basement membrane zone at the dermal-epidermal junction at E11.5 (Fig. 6 A), E15.5 (Fig. 6 C), and E17.5 (Fig. 6 E). Type VII collagen was detected throughout the dermis at each of these stages, as it was at birth, but it became more concentrated in the basement membrane zone as development proceeded (compare Fig. 6 B, D, and F). The distribution of fibronectin at each stage was similar to that seen at birth; fibronectin was detected throughout the dermis up to the dermal-epidermal junction, and in some sections it was considerably more concentrated at this junction (data not shown), as reported previously (Peters and Hynes, 1996).


alpha3beta1 Integrin is required for normal development of the epidermal basement membrane.

DiPersio CM, Hodivala-Dilke KM, Jaenisch R, Kreidberg JA, Hynes RO - J. Cell Biol. (1997)

Distributions of entactin  and type VII collagen in the developing skin. Frozen sections from  mouse embryonic skin at days E11.5  (A and B), E15.5 (C and D), or  E17.5 (E and F) of development  were stained with antisera against  entactin (A, C, and E) or type VII  collagen (B, D, and F). Staining patterns for entactin or type VII collagen were identical in wild-type (A,  C, and D) and heterozygous (E and  F) embryos; type VII collagen staining in B is from an α3-, E11.5  embryo, but was identical to that of  a wild-type embryo at this stage. e,  epidermis; d, dermis. Bar, 50 μm.
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Related In: Results  -  Collection

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Figure 6: Distributions of entactin and type VII collagen in the developing skin. Frozen sections from mouse embryonic skin at days E11.5 (A and B), E15.5 (C and D), or E17.5 (E and F) of development were stained with antisera against entactin (A, C, and E) or type VII collagen (B, D, and F). Staining patterns for entactin or type VII collagen were identical in wild-type (A, C, and D) and heterozygous (E and F) embryos; type VII collagen staining in B is from an α3-, E11.5 embryo, but was identical to that of a wild-type embryo at this stage. e, epidermis; d, dermis. Bar, 50 μm.
Mentions: The developmental expression and general distributions of several ECM proteins were identical in skin from wildtype, heterozygous, and α3- embryos at each developmental stage examined; therefore, panels in Fig. 6 show representative data for entactin and type VII collagen. Entactin clearly defined a basement membrane zone at the dermal-epidermal junction at E11.5 (Fig. 6 A), E15.5 (Fig. 6 C), and E17.5 (Fig. 6 E). Type VII collagen was detected throughout the dermis at each of these stages, as it was at birth, but it became more concentrated in the basement membrane zone as development proceeded (compare Fig. 6 B, D, and F). The distribution of fibronectin at each stage was similar to that seen at birth; fibronectin was detected throughout the dermis up to the dermal-epidermal junction, and in some sections it was considerably more concentrated at this junction (data not shown), as reported previously (Peters and Hynes, 1996).

Bottom Line: Laminin-5 and other matrix proteins remained associated with both the dermal and epidermal sides of blisters, suggesting rupture of the basement membrane itself, rather than detachment of the epidermis from the basement membrane as occurs in some blistering disorders such as epidermolysis bullosa.Consistent with this notion, primary keratinocytes from alpha3beta1-deficient skin adhered to laminin-5 through alpha6 integrins.However, alpha3beta1-deficient keratinocytes spread poorly compared with wild-type cells on laminin-5, demonstrating a postattachment requirement for alpha3beta1 and indicating distinct roles for alpha3beta1 and alpha6beta4.

View Article: PubMed Central - PubMed

Affiliation: Center for Cancer Research, and Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA.

ABSTRACT
Integrins alpha3beta1 and alpha6beta4 are abundant receptors on keratinocytes for laminin-5, a major component of the basement membrane between the epidermis and the dermis in skin. These integrins are recruited to distinct adhesion structures within keratinocytes; alpha6beta4 is present in hemidesmosomes, while alpha3beta1 is recruited into focal contacts in cultured cells. To determine whether differences in localization reflect distinct functions of these integrins in the epidermis, we studied skin development in alpha3beta1-deficient mice. Examination of extracellular matrix by immunofluorescence microscopy and electron microscopy revealed regions of disorganized basement membrane in alpha3beta1-deficient skin. Disorganized matrix was first detected by day 15.5 of embryonic development and became progressively more extensive as development proceeded. In neonatal skin, matrix disorganization was frequently accompanied by blistering at the dermal-epidermal junction. Laminin-5 and other matrix proteins remained associated with both the dermal and epidermal sides of blisters, suggesting rupture of the basement membrane itself, rather than detachment of the epidermis from the basement membrane as occurs in some blistering disorders such as epidermolysis bullosa. Consistent with this notion, primary keratinocytes from alpha3beta1-deficient skin adhered to laminin-5 through alpha6 integrins. However, alpha3beta1-deficient keratinocytes spread poorly compared with wild-type cells on laminin-5, demonstrating a postattachment requirement for alpha3beta1 and indicating distinct roles for alpha3beta1 and alpha6beta4. Our findings support a novel role for alpha3beta1 in establishment and/or maintenance of basement membrane integrity, while alpha6beta4 is required for stable adhesion of the epidermis to the basement membrane through hemidesmosomes.

Show MeSH
Related in: MedlinePlus