αPS1βPS integrin receptors regulate the differential distribution of Sog fragments in polarized epithelia

Abstract

Bone morphogenetic proteins (BMPs) have important functions during epithelial development. In Drosophila, extracellular Short gastrulation (Sog) limits the action of the BMP family member Decapentaplegic (Dpp). We have shown that Integrin receptors regulate Sog activity and distribution during pupal wing development to direct placement of wing veins. Here, we show that Integrins perform a similar function in the follicular epithelium, impacting Dpp function during oogenesis and embryonic development. As reported for the wing, this effect is specific to mew, which codes for alphaPS1 integrin. Sog is subject to cleavage by metalloproteases, generating fragments with different properties. We also show that Integrins regulate the distribution of C- and N-terminal Sog fragments in both epithelia, suggesting they may regulate the quality of BMP outputs. Our data indicate that alphaPS1betaPS integrin receptors regulate the amount and type of Sog fragments available for diffusion in the extracellular space during oogenesis and pupal wing development.

Position matters: Variability in the spatial pattern of BMP modulators generates functional diversity

“…For instance, a CR1-only containing N-terminal Sog fragment (Supersog) is a broader BMP antagonist than full length Sog, inhibiting both dpp and gbb in the wing (Yu et al, 2000). We have reported the differential diffusion of Sog fragments in the extracellular space, with N-terminal Sog fragments containing CR1 displaying limited diffusion, while C-terminal fragments diffuse a significant distance during oogenesis and in the pupal wing (Carneiro et al, 2006;Negreiros et al, 2010). Furthermore, Tld and Tlr display differential preference for Sog cleavage sites (Serpe et al, 2005), suggesting that the pattern of Sog fragments and thus Sog activity generated by the action of each metalloprotease may differ.…”

“…On the dorsal surface, a heterodimer formed by the b integrin subunit encoded by myospheroid (mys) and the a subunit encoded by multiple edematous wing (mew), controls the spread of Sog towards the provein territory (Araujo et al, 2003). In wild type wings C-terminal Sog fragments are able to diffuse, while N-terminal fragments that antagonize BMPs do not enter the provein domain, remaining restricted to intervein cells (Negreiros et al, 2010), either present at the cell surface or internalized by endocytic events. Adjacent to clones of cells that do not express either mys or mew C-terminal Sog does not enter the provein domain to concentrate Dpp, resulting in veins that diverge towards the clone (Araujo et al, 2003).…”

“…Adjacent to clones of cells that do not express either mys or mew C-terminal Sog does not enter the provein domain to concentrate Dpp, resulting in veins that diverge towards the clone (Araujo et al, 2003). mew and mys also regulate Sog distribution in ventral regions of the egg chamber, where tld and tlr are expressed (Carneiro et al, 2006;Negreiros et al, 2010). This suggests that integrins control the differential distribution of Sog fragments generated by metalloproteases during pupal wing development and oogenesis.…”

“…Over-expression of Drosophila palmitoylase dHIP14 mimics Sog activity in vivo, generating a vein loss phenotype in the wing and a loss of peak pMad staining in the embryo. It is possible that palmitoylation contributes to the differential mobility observed in vivo for Sog fragments (Carneiro et al, 2006;Negreiros et al, 2010), by allowing cleavage of Sog at the membrane and generating tethered N-terminal Supersog (Yu et al, 2000) plus a freely diffusible C-terminal fragment.…”

“…Tld is expressed at low levels in intervein cells, together with widespread Gbb and complementary to the source of Dpp (Araujo et al, 2003;Conley et al, 2000). Although Sog cleavage by metalloproteases is greater in the presence of Dpp (Shimmi and O'Connor, 2003), cleavage of Sog by Tld or by a yet to be identified protease does take place in the intervein region: C-terminal Sog fragments are distinguished emanating from intervein cells towards the provein domain while N-terminal fragments remain restricted to the intervein region (Araujo et al, 2003;Negreiros et al, 2010). Furthermore, Sog fragments display antagonistic functions in the pupal wing: N-terminal fragments act locally to antagonize BMPs while Cterminal fragments diffuse and have a pro-BMP action (Negreiros et al, 2010).…”