Regulatory layers of robustness of CLAVATA-WUSCHEL feedback system in stem cell homeostasis

Spatio-temporal regulation of gene expression and cellular behavior is critical for ensuring developmental robustness in all multicellular organisms. The mechanisms regulating robustness are often multilayered, with underlying processes occurring at different spatio-temporal scales. Pluripotent stem cells are maintained in SAMs despite periodic differentiation of stem-cell progeny into all above-ground organs, which together form much of the biomass on Earth. Shoot apical meristems (SAMs) are often exposed to variable growth conditions in nature; therefore, stem cell maintenance must be robust to withstand these changes. We focus our review on the mechanisms that regulate the robustness of the central CLAVATA (CLV)-WUSCHEL (WUS) feedback system, highlighting insights from new studies that integrate biological experiments with mathematical modeling. These studies have revealed the importance of WUS concentration-dependent transcription of <i>CLV3</i> involving cis-regulatory module and WUS-binding cofactors, CLV3 peptide processing and modifications, multiple signals converging on <i>WUS</i> transcriptional regulation, and WUS protein in regulating its subcellular partitioning, diffusion between adjacent cells, and degradation. We discuss mechanisms that could provide robustness to each of these processes and how their integration could provide tissue-level robustness in stem cell maintenance.