Daughter Cell Identity Emerges from the Interplay of Cdc42 Septins and Exocytosis

摘要

class="head no_bottom_margin" id="sec1title">IntroductionAsymmetric cell division plays a key role in differential inheritance of cell fate determinants and segregation of damaged material to one daughter cell (). Budding yeast, in which mother and daughter possess distinct developmental programs and replicative life spans, provides an important model system to study molecular mechanisms of cell fate differentiation. To prevent intermixing of material between cells sharing contiguous membranes, diffusion barriers, recently associated with septin cytoskeleton (), are required. Septins are conserved GTP-binding proteins that form hetero-oligomeric complexes capable of assembling into higher-order structures, such as filaments, rings, and gauzes (). They play important roles in diverse cellular functions and human diseases, including polarized cell growth, cytokinesis, mitosis, cell migration, bacterial infection, cancer, and neurodegenerative diseases (). Diffusion barriers based on polymeric septin rings are found not only at the division site of fungal cells but also at the base of primary cilia, dendritic spines, and in the annuli of sperm tails (). However, the mechanisms underlying septin ring biogenesis remain unknown in any system.In budding yeast, five mitotic septins (Cdc3, Cdc10, Cdc11, Cdc12, and Shs1) form rod-shaped hetero-oligomeric complexes, which polymerize into filaments that further organize into a ring structure at the presumptive bud site (PBS) (). Upon bud emergence, the septin ring matures into a collar that is localized at the narrow neck between mother and daughter. Recently, using polarized fluorescence microscopy and cryo-electron tomography, much progress has been made in understanding the ultrastructure of the septin ring and collar (). Despite careful description of septin accumulation at the PBS () and the demonstration of the essential role of Cdc42 in this process (), the precise molecular mechanisms that control septin ring formation, its position and size, remain poorly understood. Thus, it is still unclear what makes the accumulating septin polymers form a ring ().Here, we demonstrate that septin ring formation is equivalent to the emergence of a qualitatively distinct membrane domain that is destined to become a daughter cell. We discover a crucial role of exocytosis in shaping septins into a ring and demonstrate that interlinked feedback loops between Cdc42 activity, septins, and exocytosis are essential for this process. We develop a whole-cell systems biology model that integrates the formation of the Cdc42 cluster, recruitment of septins, and exocytosis to explain the simultaneous emergence of the septin ring and the nascent bud as a single morphogenetic event that differentiates daughter from mother long before cytokinesis separates them irreversibly.