| Abstract |
Basal lamina (Basement membrane) is a special category of extracellular matrix, discerned by electron microscopy into three zones, Lamina lucida, Lamina densa and Sub Lamina densa. This distinguishable extracellular matrix underlies all external and internal epithelia, covers endothelia towards the connective tissue and surrounds nerves, muscles and fat cells. Besides the connection with the underlying mesenchyme and the structural support that provides to different tissues, many various functions have been assigned to the basement membranes. These include a physical barrier for passage of macromolecules, cells or nervoprocesses, binding and deposition of growth factors and hormones and specification of cell migration, proliferation and metabolism. Skin-basement membrane (Dermal Epidermal Junction, DEJ) separates dermis from epidermis but in the same time contributes to their adherent connection, resulting in the structural integrity of the skin. Skin-basal lamina is composed mainly of laminins 5, 6, 10 ,1, collagen IV and VII, nidogen and perlecan, that are arranged in an ordered fashion building a highly specialized ultrastructure (which is connected with dermis and basal keratinocytes). Different skin disorders in human have been associated with defects in the genes encoding some components of the basement membrane. These defects usually lead postnatally, to the loss of adherence of epidermis to dermis and subsequently to the formation of subepidermal blisters. Inactivation of the same genes in mice results in parallel symptoms. The present study is an investigation of the function of a new gene in mouse, called Fras1. The Fras1 gene encodes for a protein of 4010 amino acids, which can be subdivided in several distinct domains. During embryonic development Fras1 expression is confined to different epithelial cell layers, while Fras1 is detected extracellularly producing a linear staining pattern underlying epidermis as well as the basal surface of several epithelia. Loss of Fras1 function results in the formation of subepidermal hemorrhagic blisters as well as in unilateral or bilateral renal agenesis during mouse embryogenesis. Postnatally, homozygous Fras1 mutants exhibit fusion of the eyelids and digits, skeletal abnormalities, as well as unilateral renal agenesis or dysplasia. On the basis of the observed investigations, it is deciphered that Fras1 is involved in a structural scaffold that arranges the assembly of at least some of the macromolecules of the dermal side of skin basement membrane, affecting the dermal epidermal connection underneath the lamina densa. Therefore its absence causes, under certain circumstances, subepidermal blister formation and skin detachment underneath Lamina densa. Additionally, our data demonstrate that inactivation of Fras1 is correlated with the existing Blebbed mouse mutant, which have been suggested to provide a model for the human genetic disorder Fraser syndrome and that perturbations in the composition of the extracellular space underlying epithelia could account for the onset of both of the above anomalies.
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