Mesenchymal-to-epithelial transitions require tissue-specific interactions with distinct laminins

Abstract

Mesenchymal-to-epithelial transition (MET) converts cells from migratory mesenchymal to polarized epithelial states. Despite its importance for both normal and pathological processes, very little is known about the regulation of MET in vivo. Here we exploit midgut morphogenesis in Drosophila melanogaster to investigate the mechanisms underlying MET. We show that down-regulation of the EMT transcription factor Serpent is required for MET, but not sufficient, as interactions with the surrounding mesoderm are also essential. We find that midgut MET relies on the secretion of specific laminins via the CopII secretory pathway from both mesoderm and midgut cells. We show that secretion of the laminin trimer containing the Wingblister α-subunit from the mesoderm is an upstream cue for midgut MET, leading to basal polarization of αPS1 integrin in midgut cells. Polarized αPS1 is required for the formation of a monolayered columnar epithelium and for the apical polarization of αPS3, Baz, and E-Cad. Secretion of a distinct LamininA-containing trimer from midgut cells is required to reinforce the localization of αPS1 basally, and αPS3 apically, for robust repolarization. Our data suggest that targeting these MET pathways, in conjunction with therapies preventing EMT, may present a two-pronged strategy toward blocking metastasis in cancer.

Regulation and Function of Laminin A5 during Mouse and Human Decidualization

“…Laminins bind laminin-specific receptors to maintain the integrity of epithelium [ 49 ]. Recent reports suggest that laminins regulate MET in Drosophila [ 50 ]. Therefore, laminin α5β2γ1 might be involved in MET.…”

De novo apical domain formation inside the Drosophila adult midgut epithelium

“…Enteroblasts then re-polarise once they reach the septate junctions between the overlying enterocytes. Thus, the adult enteroblasts go through a similar set of transitions to the embryonic midgut precursors, which undergo an epithelial to mesenchymal transition when they delaminate from the primary epithelium and become migratory, before re-polarising in contact with the visceral mesoderm to form the embryonic midgut epithelium(Campbell et al, 2011; Pitsidianaki et al ., 2021; Tepass and Hartenstein, 1994).…”

“…The adult midgut epithelium differs from all other Drosophila epithelia in several key respects. Firstly, it is a secondary epithelium that is derived from the endoderm, in contrast to most Drosophila epithelia which are directly descend from the cellular blastoderm epithelium(Pitsidianaki et al, 2021; Tepass and Hartenstein, 1994; Yarnitzky and Volk, 1995). Secondly, the apical-basal polarity of the epithelium does not require the conserved epithelial polarity factors that polarize all ectodermal and mesodermal epithelia, although most of these factors are expressed in the midgut.…”

Won’t You be My Neighbor: How Epithelial Cells Connect Together to Build Global Tissue Polarity

“…While the components of apical, junctional, lateral, and basal complexes are broadly conserved, the initial establishment of apico-basolateral polarity is context dependent ( Pickett et al, 2019 ): for instance, the polarization of the C. elegans intestine depends upon the presence of the conserved protein scaffold PAR-3, while the C. elegans epidermis can polarize in the absence of PAR-3 ( Achilleos et al, 2010 ). During fly gut development, ectodermally-derived epithelial tissues such as the hindgut, require the apical polarity determinant Crumbs while endodermally-derived midgut cells lose Crumbs expression ( Tepass et al, 1990 ; Campbell et al, 2011 ) and instead rely on interactions with underlying laminin to correctly polarize ( Tepass and Hartenstein, 1994 ; Yarnitzky and Volk, 1995 ; Pitsidianaki et al, 2021 ). Regardless of the mechanism for apico-basolateral polarity establishment within cells, molecular circuits maintain polarity through positive feedback and mutual antagonism of apical, junctional, lateral, and basal protein complexes ( Pickett et al, 2019 ; Buckley and St Johnston, 2022 ).…”

“…In the absence of laminin, but not other basement membrane components, C. elegans pharyngeal cells no longer polarize towards a central common midline to form one lumen but rather invert their apico-basolateral polarity, leading to the formation of two lumens ( Rasmussen et al, 2012 ). In developing Drosophila midgut, a specific laminin subunit secreted by the underlying mesoderm is required for the re-polarization of migrating endodermal cells ( Pitsidianaki et al, 2021 ). In the adult Drosophila midgut, intercalating intestinal stem cells do not require any of the known canonical apical, junctional, or basolateral polarity complexes to establish apico-basolateral polarity, but do rely upon basal integrin signaling to polarize as these cells differentiate into enterocytes and join the intestinal epithelium ( Chen et al, 2018 ).…”