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© The Rockefeller University Press, 0021-9525/1997//729 $5.00
The Journal of Cell Biology, Volume 137, Number 3, , 1997 729-742

Article

{alpha}3β1 Integrin Is Required for Normal Development of the Epidermal Basement Membrane



C. Michael DiPersio*, Kairbaan M. Hodivala-Dilke*, Rudolf Jaenisch§, Jordan A. Kreidberg{ddagger}, and Richard O. Hynes*

* Howard Hughes Medical Institute, Center for Cancer Research, and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; {ddagger} Divisions of Nephrology and Newborn Medicine, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115; and § Whitehead Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Integrins {alpha}3β1 and {alpha}6β4 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; {alpha}6β4 is present in hemidesmosomes, while {alpha}3β1 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 {alpha}3β1-deficient mice. Examination of extracellular matrix by immunofluorescence microscopy and electron microscopy revealed regions of disorganized basement membrane in {alpha}3β1-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 {alpha}3β1-deficient skin adhered to laminin-5 through {alpha}6 integrins. However, {alpha}3β1-deficient keratinocytes spread poorly compared with wild-type cells on laminin-5, demonstrating a postattachment requirement for {alpha}3β1 and indicating distinct roles for {alpha}3β1 and {alpha}6β4. Our findings support a novel role for {alpha}3β1 in establishment and/or maintenance of basement membrane integrity, while {alpha}6β4 is required for stable adhesion of the epidermis to the basement membrane through hemidesmosomes.

1. Abbreviations used in this paper: ECM, extracellular matrix; HEK, human epidermal keratinocytes; JEB, junctional epidermolysis bullosa.

This research was supported by a grant from the National Institutes of Health (RO1CA17007) to R.O. Hynes. K.M. Hodivala-Dilke was supported by the International Human Frontier Science Program. R.O. Hynes is an Investigator of the Howard Hughes Medical Institute.

The first two authors contributed equally to the work presented.

Please address all correspondence to R.O. Hynes, Howard Hughes Medical Institute, Center for Cancer Research, and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139. Tel.: (617) 253-6422. Fax: (617) 253-8357.


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