White Matthew J, Jacobs Kyle A, Singh Tania, Kutys Matthew L
Department of Cell and Tissue Biology, University of California San Francisco, San Francisco CA, 94143, USA.
Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco CA, 94143, USA.
bioRxiv. 2023 Jan 23:2023.01.23.524428. doi: 10.1101/2023.01.23.524428.
Notch receptors control tissue morphogenic processes that involve coordinated changes in cell architecture and gene expression, but how a single receptor can produce these diverse biological outputs is unclear. Here we employ a 3D organotypic model of a ductal epithelium to reveal tissue morphogenic defects result from loss of Notch1, but not Notch1 transcriptional signaling. Instead, defects in duct morphogenesis are driven by dysregulated epithelial cell architecture and mitogenic signaling which result from loss of a transcription-independent Notch1 cortical signaling mechanism that ultimately functions to stabilize adherens junctions and cortical actin. We identify that Notch1 localization and cortical signaling are tied to apical-basal cell restructuring and discover a Notch1-FAM83H interaction underlies stabilization of adherens junctions and cortical actin. 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.
Notch受体控制着涉及细胞结构和基因表达协调变化的组织形态发生过程，但单个受体如何产生这些多样的生物学输出尚不清楚。在这里，我们采用导管上皮的三维器官型模型来揭示组织形态发生缺陷是由Notch1的缺失导致的，而非Notch1转录信号的缺失。相反，导管形态发生缺陷是由上皮细胞结构失调和有丝分裂信号驱动的，这些是由于转录非依赖性Notch1皮质信号机制的丧失所致，该机制最终起到稳定黏着连接和皮质肌动蛋白的作用。我们确定Notch1的定位和皮质信号与顶-基细胞重组相关，并发现Notch1与FAM83H的相互作用是黏着连接和皮质肌动蛋白稳定的基础。这些结果共同为Notch1信号传导和调控提供了新见解，并推进了一种范式，即转录和细胞黏附程序可能由单个受体协调。
