Metabolic control of YAP via the acto-myosin system during liver regeneration

Abstract

15The mechanisms of organ size control remain poorly understood. A key question is how cells 16 collectively sense the overall status of a tissue. We addressed this problem focusing on mouse liver 17 regeneration, which is controlled by Hippo signalling. Using digital tissue reconstruction and 18 quantitative image analysis, we found that the apical surface of hepatocytes forming the bile 19 canalicular network expands concomitant with an increase of F-actin and phospho-Myosin, to 20 compensate an overload of bile acids. Interestingly, these changes are sensed by the Hippo 21 transcriptional co-activator YAP, which localizes to the apical F-actin-rich region and translocates to 22 the nucleus in dependence of the acto-myosin system. This mechanism tolerates moderate bile acid 23 fluctuations under tissue homeostasis, but activates YAP in response to sustained bile acid overload. 24Using an integrated biophysical-biochemical model of bile pressure and Hippo signalling, we explained 25 this behaviour by the existence of a mechano-sensory mechanism that activates YAP in a switch-like 26 manner. We propose that the apical surface of hepatocytes acts as a self-regulatory mechano-sensory 27 system that responds to critical levels of bile acids as readout of tissue status. 28 29 Several signalling pathways are required for liver regeneration (9,10) of which the Hippo pathway is a 52 key regulator of liver size (11,12). The Hippo pathway is activated during liver regeneration (13) to 53 promote hepatocyte proliferation primarily via the co-transcriptional activator yes-associated protein 54 (YAP). It is a mechano-sensor for signals from the actin cytoskeleton, cell polarity complexes and cell-55 cell or cell-matrix junctions (14-16) and is also responsive to high concentrations of bile acids (BA) 56 (17). Despite these molecular insights, how cells sense the overall tissue status and size remains an 57 open question. In particular, it is unclear how cells integrate metabolic (BA levels) and/or mechanical 58 alterations, like changes in blood and bile pressure, to control liver size during homeostasis and 59 regeneration. Here, we addressed these questions by applying high-resolution microscopy and 60 quantitative 3D image analysis (18,19) to explore tissue and cellular alterations during liver 61 regeneration. 62 63 Results 64Alterations of the BC network during liver regeneration 65

YAP vs. TAZ: differences in expression revealed through rigorous validation of target-specific monoclonal antibodies

“…Under growth-promoting conditions, YAP and TAZ have been reported to translocate from the cytoplasm to the nucleus where they interact with TEA-domain containing (TEAD) transcription factors to regulate the transcription of genes, many of which govern cell proliferation and apoptosis [24][25][26][27]. As such, YAP and TAZ have been strongly implicated in tissue growth, repair, and regeneration [28][29][30][31][32][33][34][35][36], and their dysregulation has been associated with tumor development in a variety of tissue types [22,25,37].…”