Abstract
ABSTRACTA switch from E- to N-cadherin regulates the transition from pluripotency to neural identity, but the mechanism by which cadherins regulate differentiation was previously unknown. Here, we show that the acquisition of N-cadherin stabilises neural identity by dampening anti-neural signals. We use quantitative image analysis to show that N-cadherin promotes neural differentiation independently of its effects on cell cohesiveness. We reveal that cadherin switching diminishes the level of nuclear β-catenin, and that N-cadherin also dampens FGF activity and consequently stabilises neural fate. Finally, we compare the timing of cadherin switching and differentiation in vivo and in vitro, and find that this process becomes dysregulated during in vitro differentiation. We propose that N-cadherin helps to propagate a stable neural identity throughout the emerging neuroepithelium, and that dysregulation of this process contributes to asynchronous differentiation in culture.
Highlights
There is an increasing appreciation that changes in adhesion and morphology help to regulate cell fate changes (Gilmour et al, 2017)
Upregulation of N-cadherin accompanies the loss of E-cadherin as pluripotent cells adopt a neural fate (Dady et al, 2012; Hatta and Takeichi, 1986), raising the possibility that N-cadherin might contribute to the regulation of the differentiation process
It has previously been reported that premature cadherin switching results in gross morphological and cell-fate allocation defects at gastrulation, resulting at least in part from defects in extraembryonic tissues (Basilicata et al, 2016)
Summary
There is an increasing appreciation that changes in adhesion and morphology help to regulate cell fate changes (Gilmour et al, 2017). It has previously been reported that premature cadherin switching has profound effects at gastrulation, including an expansion of the extra-embryonic compartment, a reduction in the size of the epiblast, and mispatterning of the germ layers (Basilicata et al, 2016). These diverse phenotypes can be attributed, at least in part, to an overall reduction in BMP signalling within the epiblast and a reduction in pro-mesoderm signals at the primitive streak, which in turn may result from the gross morphological defects seen in these embryos (Basilicata et al, 2016). We use cultured mouse pluripotent cells in order to focus on the mechanism by which cadherin switching influences neural differentiation of pluripotent cells in the absence of extra-embryonic tissues
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