Differential localization profile of Fras1/Frem proteins in epithelial basement membranes of newborn and adult mice

Abstract

The Fras1/Frem gene family encodes for structurally similar proteins of the extracellular matrix, functionally correlated with embryonic dermal-epidermal adhesion as deduced from the appearance of sub-epidermal blisters in mouse mutants compromising the function of Fras1, Frem1 and Frem2 proteins. Mutations in the human counterparts FRAS1 and FREM2 have been detected in patients suffering from Fraser syndrome. So far, Fras1/Frem proteins have been shown to be strictly colocalized in the sublamina densa of mouse epithelial basement membranes during development. Here, we focused on the characterization of the localization pattern of the aforementioned proteins, in various parts of the adult mouse skin as well as a range of organs and tissues. Frem3 was present in a broad range of epithelial basement membranes where Fras1, Frem1 and Frem2 were missing. The localization profile of Frem3 coincided with that of collagen VII in all skin basement membranes but differed in that Frem3 was additionally found in the basement membrane of several internal epithelia, where collagen VII was absent. Fras1 and Frem2 were colocalized with Frem3 in the basement membrane of certain skin parts, underlying the thin-layer, of rapidly proliferating keratinocytes, whereas Frem1 was detected only in the basement membrane of the tail. The localization pattern of Fras1 and Frem2 was indistinguishable, while both proteins along with Frem3 could be detected even in the absence of Frem1.

Basement membranes in development and disease

“…Fras1, Frem2, and Frem1 all localize to the BM, where the proteins are thought to form an oligomeric complex required for their reciprocal stabilization at this location (Kiyozumi et al, 2006), although differences in tissue specific expression between the genes suggest that they may have independent functions (Petrou et al, 2007a,b;Pavlakis et al, 2008). This means to an extent that the phenotypes derived from mutation of one of these components might actually reflect a loss or partial loss of all three species.…”

Syndactyly in a novel Fras1rdf mutant results from interruption of signals for interdigital apoptosis

“…Fras1 is expressed in the epidermis throughout the body including the limb bud (Vrontou et al, ; Chiotaki et al, ; Petrou et al, ; Pavlakis et al, ). However, blisters were only found in selected tissues in Fras1 mutants.…”

“…FRAS1 can associate with other matrix molecules including FREM1 and FREM2 to provide early adhesion during basement membrane formation (McGregor et al, ; Vrontou et al, ; Kiyozumi et al, ). Fras1 is expressed by epithelial cells at sites of epithelial‐mesenchyme interfaces, including in the epidermis covering most of the body, including the limb and eye, as well as in the kidney and lung (Vrontou et al, ; Chiotaki et al, ; Petrou et al, ; Pavlakis et al, ). Expression in these tissues begins as early as embryonic day 10.5 (E10.5), and in most tissues the expression level tapers off near birth (Short et al, ).…”

Extending the knowledge in histochemistry and cell biology

“…The authors therefore cautioned to use black or white answers for the function of nidogen and perlecan. A detailed investigation on the ECM proteins Fras1/Frem in epithelial BMs of newborn and adult mice has been provided by Pavlakis et al (2008). Mutations in the human counterparts FRAS1 and FREM2 have been detected in patients suVering from Fraser syndrome (Short et al 2007).…”