Abstract
The atypical cadherins Fat and Dachsous (Ds) have been found to underlie planar cell polarity (PCP) in many tissues. Theoretical models suggest that polarity can arise from localized feedbacks on Fat-Ds complexes at the cell boundary. However, there is currently no direct evidence for the existence or mechanism of such feedbacks. To directly test the localized feedback model, we developed a synthetic biology platform based on mammalian cells expressing the human Fat4 and Ds1. We show that Fat4-Ds1 complexes accumulate on cell boundaries in a threshold-like manner and exhibit dramatically slower dynamics than unbound Fat4 and Ds1. This suggests a localized feedback mechanism based on enhanced stability of Fat4-Ds1 complexes. We also show that co-expression of Fat4 and Ds1 in the same cells is sufficient to induce polarization of Fat4-Ds1 complexes. Together, these results provide direct evidence that localized feedbacks on Fat4-Ds1 complexes can give rise to PCP.
Highlights
Planar cell polarity (PCP) defines the coordinated polarization of cells in the plane of a tissue (Adler, 2002; Lewis and Davies, 2002; Lawrence et al, 2007; Wang and Nathans, 2007; Goodrich and Strutt, 2011) and underlies the organization and geometry required for the proper function of many developing organs
PCP is defined by asymmetric distribution of transmembrane protein complexes which belong to two families - the Frizzled/Van-Gogh pathway and the Fat/Dachsous (Ft/Ds) pathway
We further show that Fat4-Ds1 complexes at the cell boundary form extremely stable clusters, suggesting that complex stabilization through clustering may serve as a mechanism for localized feedback
Summary
Planar cell polarity (PCP) defines the coordinated polarization of cells in the plane of a tissue (Adler, 2002; Lewis and Davies, 2002; Lawrence et al, 2007; Wang and Nathans, 2007; Goodrich and Strutt, 2011) and underlies the organization and geometry required for the proper function of many developing organs. PCP is defined by asymmetric distribution of transmembrane protein complexes which belong to two families - the Frizzled/Van-Gogh pathway (termed the ‘core’ pathway) and the Fat/Dachsous (Ft/Ds) pathway. Both were discovered in Drosophila but are conserved in higher vertebrates (Goodrich and Strutt, 2011; Singh and Mlodzik, 2012; Sharma and McNeill, 2013). Unlike for classical cadherins, there is no evidence of homophilic complexes of either Ft or Ds forming across cells (Matakatsu and Blair, 2004; Matis and Axelrod, 2013)
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