Assistant Professor University of California San Francisco San Francisco, California, United States
Introduction:: The coordination of genetic programs and the physical organization of cells sculpt developing tissues, drive regeneration and, when dysregulated, facilitate disease. Exchange of chemical and mechanical information at cell-cell interfaces necessarily coordinates these processes, though molecular details remain unclear. The ubiquitously important Notch pathway mediates cell-to-cell communication in a variety of tissues across developmental stages. Recent work from our group and others have contributed to an emerging model in which Notch receptor activation can regulate both cell mechanics and transcriptional changes.
Materials and Methods:: Here, employing an organotypic tissue-engineered model of a human mammary ductal epithelium in combination with genetic approaches to specifically isolate the mechanical and transcriptional arms of Notch signaling, we observe that deletion of NOTCH1 results in the morphogenic dysregulation of duct tissue architecture that is not observed upon loss of Notch1 transcriptional activity.
Results, Conclusions, and Discussions:: We define the mechanistic underpinnings of this mechanical role of Notch1, which we term cortical Notch1 signaling, and demonstrate its capacity to regulate epithelial cell-cell adhesion by influencing cortical tension. Together, these results offer new insights into Notch1 signaling and regulation, and advance a paradigm in which transcriptional and cell adhesive programs might be coordinated by a single receptor.
