Abstract
Cadherin switching from E-cadherin (E-cad) to N-cadherin (N-cad) is a key step of the epithelial-mesenchymal transition (EMT) processes that occurs during gastrulation and cancer progression. We investigate whether cadherins actively participate in progression of EMT by crosstalk to signaling pathways. We apply ectopic cadherin switching before the onset of mouse gastrulation. Mutants with an induced E-cad to N-cad switch (Ncadki) die around E8.5. Severe morphological changes including a small epiblast, a rounded shape, an enlarged extra-embryonic compartment and lack of the amnion, combined with a massive cell detachment from the ectodermal layer are detected. In contrast to epiblast-specific E-cad depletion, gastrulation is initiated in Ncadki embryos, but patterning of the germ-layers is abnormal. An overall reduction in BMP signaling, expansion of Nodal and Eomes domains, combined with reduced Wnt3a expression at the primitive streak is observed. Our results show that in addition to cadherin-dependent adhesion, proper embryonic development requires E-cad mediated signaling function to facilitate a feedback loop that stabilizes Bmp4 and Bmp2 expression in the extraembryonic ectoderm and sustained downstream activity in the epiblast. Moreover, for proper morphogenesis a fine-tuned spatio-temporal control of cadherin switching is required during EMT at gastrulation to avoid premature cell detachment and migration.
Highlights
During mammalian development as well as during cancer progression epithelial-mesenchymal transition (EMT) plays a crucial role to enable cell migration and change cell phenotypes and characteristics
In order to experimentally control the cadherin switch isolated from a complete EMT program, we made use of a gene replacement approach
The N-cad staining of the epiblast of the mutants showed a similar distribution as E-cad in controls, whereas neither E-cad nor N-cad staining was detected in epiblasts of Ecadnull embryos (Fig. S1C)
Summary
During mammalian development as well as during cancer progression EMT plays a crucial role to enable cell migration and change cell phenotypes and characteristics. They lose E-cad expression and gain expression of N-cad combined with a more spindle shape morphology, a front-rear polarity and a motile phenotype. The cadherin switch is a hallmark of EMT the role of N-cad in the process of gastrulation and mesoderm migration is not well understood. Embryos that express N-cad show altered BMP activity, resulting in an atrophied epiblast, inappropriate loss of cells into the amniotic cavity and inefficient patterning of the extraembryonic mesoderm, indicating that E-cad and a tight spatio-temporal regulation of cadherin switching is indispensable for maintaining signaling loops between embryonic and extraembryonic tissues for establishing proper BMP signaling cues during axis specification
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