Disabled-2 Is an Epithelial Surface Positioning Gene

Abstract

The formation of the primitive endoderm layer on the surface of the inner cell mass is one of the earliest epithelial morphogenesis in mammalian embryos. In mouse embryos deficient of Disabled-2 (Dab2), the primitive endoderm cells lose the ability to position on the surface, resulting in defective morphogenesis. Embryonic stem cells lacking Dab2 are also unable to position on the surface of cell aggregates and fail to form a primitive endoderm outer layer in the embryoid bodies. The cellular function of Dab2, a cargo-selective adaptor, in mediating endocytic trafficking of clathrin-coated vesicles is well established. We show here that Dab2 mediates directional trafficking and polarized distribution of cell surface proteins such as megalin and E-cadherin and propose that loss of polarity is the underlying mechanism for the loss of epithelial cell surface positioning in Dab2-deficient embryos and embryoid bodies. Thus, the findings indicate that Dab2 is a surface positioning gene and suggest a novel mechanism of epithelial cell surface targeting.Epithelial cells are positioned on the outer surface of organs or the inner surface of glandular structures and are involved in diverse physiological functions. Simple epithelia consist of monolayered cells that form a sheet through cell-cell adherens junctions and attach to a basement membrane that lies underneath (1). Epithelial cells are polarized with the apical surface exposed, or free from cell-cell contact and the basal side lying in contact with a basement membrane or stromal cells. The cellfree apical space and basal contact are unique hallmarks of an epithelium and are likely positioning cues for the surface localization of the epithelial cells (2), although the molecular details and genes critical for epithelial cell surface positioning are yet uncertain and undefined. The concept that cues are required for epithelial surface positioning is also reinforced by observations of the disorganized growth of carcinomas. Carcinoma cells can be viewed as epithelial cells that have lost their ability to perceive surface positioning cues, and the neoplastic cells no longer obey the constraint imposed by tissue organization (3).The early embryos of vertebrates, especially mammalian species, have great plasticity, and significant cell dispersal, movement, and migration occur before their final positioning and acquisition of cell fates (4). Shown in the classical cell sorting experiments by Townes and Holtfreter (5), early embryonic amphibian cells of epidermis, endoderm, mesoderm, and neural plate, if dispersed, are able to segregate spontaneously upon aggregation, indicating cell positioning is an autonomous property.The primitive endoderm of mammalian early embryos is the first typical epithelial cell type derived that is capable of producing a basement membrane (6). Recent understanding is that the primitive endoderm cells arise from the differentiation of the pluripotent cells of the inner cell mass and migrate out to the surface to form the primitive endoderm layer (7...

Stk40 links the pluripotency factor Oct4 to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation

“…2D) in chimeric EB-formation assays. This is consistent with a previously reported phenomenon that ExEn cells have an intrinsic property of surface positioning when mixed with undifferentiated ESCs in the EB-differentiation process (19).…”

On the move: endocytic trafficking in cell migration

“…Also phosphorylation of E-cadherin takes place in the context of EMT [102]. In addition, E-cadherin binds the endocytic adaptor Dab2 [103]. Growth factor signaling promotes E-cadherin endocytosis additionally by activation of RIN2, which activates Rab5 [104], and of Arf6, which recruits Nm23-H1 to facilitate dynamin-mediated endocytosis [105,106].…”

L’embryogenèse précoce des mammifères

“…En revanche, ces cellules ne sont pas positionnées à la périphérie comme le sont celles des embryons sauvages mais disposées en « poivre et sel » [41], montrant que les cellules exprimant Gata4 n'ont pas pu atteindre la surface. Des phénotypes identiques ont été observés lorsque Dab2 [42][43][44] ou le gène codant pour la chaine γ1 de la laminine 111 (LamC1) [45] sont inactivés. Dab2 est une protéine adaptatrice se liant, entre autres, aux intégrines qui sont des récepteurs des laminines.…”

“…LRP2 est stockée à l'intérieur de la cellule, probablement dans le Golgi, lorsque la cellule est interne à la MCI, puis elle migre au pôle apical du futur épithélium lorsque la cellule a atteint la surface de la cavité blastocélique [33]. Cette localisation serait sous le contrôle de Dab2 [43], qui est aussi exprimée au pôle apical des cellules, bordant la cavité blastocélique. Ainsi, la cellule prépare et stocke les protéines nécessai-res à l'endocytose de nutriments, ou à la formation de la structure épithéliale comme le collagène IV, pour être prête et fonctionnelle le plus tôt possible.…”