E- and N-cadherin drive hepatic polarity and lumen elongation via opposing effects on RhoA activity

Hepatocytes exhibit distinct polarity, forming narrow apical tubes (bile canaliculi, BCs) between adjacent cells. These structures essential to liver architecture and function. Unlike most epithelial cells, hepatocytes express both E- and N-cadherin but their functions and mechanisms remain unknown. We show that E- and N-cadherin are collectively required for hepatic polarity and BC formation but act through distinct, spatially segregated pathways. Both localize to adherens junctions; E-cadherin additionally localizes to lateral membranes and the cleavage furrow during cell division, where it promotes BC elongation and new cell-cell contact formation by controlling spindle orientation and RhoA activation via NuMA and ARHGEF17. N-cadherin maintains hepatic polarity by facilitating RhoA inactivation through the p120-catenin family member ARVCF and its partner p190B/ARHGAP5. Thus, dual cadherin expression drives hepatic polarity and BC formation by controlling RhoA activity in a coordinated but opposing manner. SummaryHayase et al. show that E-cadherin promotes bile canaliculi elongation via RhoA activation and oriented cell division, while N-cadherin maintains hepatic polarity by suppressing RhoA, revealing the function and mechanism of dual cadherin expression in hepatocytes.