Nectin also recruits partitioning defective 3 (Par3), which together
with Par6 and atypical protein kinase C forms the Par polarity
complex that establishes the apical domain, in part by recruiting
another apical determinant, the Crumbs complex, and by displacing the basolateral determinant, the Scribble complex [6]. AJ
formation promotes the formation of desmosomes, which form
electron-dense plaques between neighboring cells and are attached
to intracellular intermediate cytokeratin filaments. AJ formation
also promotes the formation of sub-apical TJs, comprised of occludin, zona occludens (ZO) proteins, and claudins (CLDN), which
are essential for restricting paracellular transport of solutes and ions
and for consolidating apical-basal polarity [1, 7].
Much attention has been paid to events occurring in the dissolution of epithelial cell-cell contacts during EMT (reviewed in [3]).
A general apical-to-basal “unzipping” mechanism has been proposed, initiating with disassembly of TJs and followed by loss of
AJs, driven by both post-translational degradation and transcriptional downregulation of E-cadherin [3]. Subsequently, desmosomes and cell-ECM contacts are dismantled, concordant with a
loss of apical-basal polarity, culminating in increased individual
motility and delamination through the underlying basement membrane. However, this model, based largely on TGF-β-treated epithelial cells in vitro, is unlikely to hold universally. For example, in
epiblast cell ingression during chick gastrulation, basement membrane breakdown is the first recognizable event in EMT, preceding
loss of AJs, TJs, and apical-basal polarity [8]. Thus, the precise
order of events is also likely to be highly dependent on the celland tissue-context.
3 EMT-MET in Development
In amniote embryogenesis, the first cells with epithelial characteristics are blastomeres of the late 8-cell stage embryo; these express
E-cadherin, which accumulates at intercellular junctions that,
together with cortical actomyosin-mediated tension, induces
“compaction” in which cells flatten together and maximize interfacial contacts. Coincident with this is the emergence of apical-basal
polarity, followed by the biogenesis of TJs and desmosomes
[9]. “Proto-epithelial” cells are thus the origin of all subsequent
cells in the organism [10]. Further cleavages lead to segregation of
the trophoectoderm epithelial lineage from the inner cell mass,
which gives rise to the epiblast. The first instance of EMT occurs
during gastrulation with the emergence of the three primitive germ
layers, where migratory epiblast cells ingress to form transient
mesenchymal mesendodermal progenitors, whereas remaining epiblast cells form ectoderm [11]. Mesodermal and endodermal cells,
through successive rounds of EMT-MET, ultimately generate the
Mechanisms of MET in Development and Cancer
45
with Par6 and atypical protein kinase C forms the Par polarity
complex that establishes the apical domain, in part by recruiting
another apical determinant, the Crumbs complex, and by displacing the basolateral determinant, the Scribble complex [6]. AJ
formation promotes the formation of desmosomes, which form
electron-dense plaques between neighboring cells and are attached
to intracellular intermediate cytokeratin filaments. AJ formation
also promotes the formation of sub-apical TJs, comprised of occludin, zona occludens (ZO) proteins, and claudins (CLDN), which
are essential for restricting paracellular transport of solutes and ions
and for consolidating apical-basal polarity [1, 7].
Much attention has been paid to events occurring in the dissolution of epithelial cell-cell contacts during EMT (reviewed in [3]).
A general apical-to-basal “unzipping” mechanism has been proposed, initiating with disassembly of TJs and followed by loss of
AJs, driven by both post-translational degradation and transcriptional downregulation of E-cadherin [3]. Subsequently, desmosomes and cell-ECM contacts are dismantled, concordant with a
loss of apical-basal polarity, culminating in increased individual
motility and delamination through the underlying basement membrane. However, this model, based largely on TGF-β-treated epithelial cells in vitro, is unlikely to hold universally. For example, in
epiblast cell ingression during chick gastrulation, basement membrane breakdown is the first recognizable event in EMT, preceding
loss of AJs, TJs, and apical-basal polarity [8]. Thus, the precise
order of events is also likely to be highly dependent on the celland tissue-context.
3 EMT-MET in Development
In amniote embryogenesis, the first cells with epithelial characteristics are blastomeres of the late 8-cell stage embryo; these express
E-cadherin, which accumulates at intercellular junctions that,
together with cortical actomyosin-mediated tension, induces
“compaction” in which cells flatten together and maximize interfacial contacts. Coincident with this is the emergence of apical-basal
polarity, followed by the biogenesis of TJs and desmosomes
[9]. “Proto-epithelial” cells are thus the origin of all subsequent
cells in the organism [10]. Further cleavages lead to segregation of
the trophoectoderm epithelial lineage from the inner cell mass,
which gives rise to the epiblast. The first instance of EMT occurs
during gastrulation with the emergence of the three primitive germ
layers, where migratory epiblast cells ingress to form transient
mesenchymal mesendodermal progenitors, whereas remaining epiblast cells form ectoderm [11]. Mesodermal and endodermal cells,
through successive rounds of EMT-MET, ultimately generate the
Mechanisms of MET in Development and Cancer
45