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3
1 Integrin Is Required for Normal Development of
the Epidermal Basement Membrane

* Howard Hughes Medical Institute, Center for Cancer Research, and Department of Biology, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139; Integrins
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
3
1 and
6
4 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;
6
4
is present in hemidesmosomes, while
3
1 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
3
1-deficient mice. Examination of
extracellular matrix by immunofluorescence microscopy and electron microscopy revealed regions of disorganized basement membrane in
3
1-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
3
1-deficient skin adhered to laminin-5 through
6 integrins. However,
3
1-deficient keratinocytes spread poorly compared with wild-type cells on laminin-5, demonstrating
a postattachment requirement for
3
1 and indicating distinct roles for
3
1 and
6
4. Our findings support a
novel role for
3
1 in establishment and/or maintenance of basement membrane integrity, while
6
4 is
required for stable adhesion of the epidermis to the
basement membrane through hemidesmosomes.
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