Abstract
Homeostasis of renewing tissues requires balanced proliferation, differentiation and movement. This is particullary important in the intestinal epithelium where lineage tracing suggests that stochastic differentiation choices are intricately coupled to position. To determine how position is achieved we followed proliferating cells in intestinal organoids and discovered that behaviour of mitotic sisters predicted long-term positioning. Normally, 70% of sisters remain neighbours while 30% lose contact separating after cytokinesis. Postmitotic placements predict differences in positions of sisters later: adjacent sisters reach similar positions; one separating sister remains close to its birthplace, the other moves upward. Computationally modelling crypt dynamics confirmed post-mitotic separation as a mechanism for placement of sisters into different niches. Separation depends on interkinetic nuclear migration, cell size, and asymmetric tethering by a basal process. These processes are altered when Adenomatous polyposis coli (Apc) is mutant and separation is lost. We conclude that post-mitotic placement enables stochastic niche exit and when defective, supports the clonal expansion of Apc mutant cells.
