Shortly thereafter, the lumens of developing nephron tubules become continuous, and further elongation of the lumen coincides with elongation of the tubule ( Yang et al., 2013). In previous studies, we have shown that once a lumen is created, elongation initially occurs by simultaneous extension of the lumen and additional de novo lumen generation ( Yang et al., 2013). Study of this process serves as an excellent model to elucidate mechanisms of polarization and tubulogenesis. Whereas the latter arises as a branch from a pre-existing tubule, the cap mesenchyme must undergo a mesenchymal-to-epithelial transition to form a nascent epithelial tubule with de novo establishment of apical-basal polarity and generation of a lumen. The cap mesenchyme gives rise to nephron segments from the glomerulus to the distal tubule, and the ureteric epithelium becomes the collecting duct. In the developing kidney, epithelial tubules are derived from progenitor cells from two embryonic sources: the cap mesenchyme and the ureteric epithelium ( Saxen, 1987). Additionally, the individually polarized cells must coordinate their polarity with surrounding cells along the long axis of the tubule, in a process referred to as planar cell polarity. The apical surface faces the luminal space, the lateral surface contacts adjacent cells, and the basal surface contacts the basal lamina. An epithelial cell can polarize along its apical-basal axis, which orients the cell relative to the underlying extracellular matrix. Despite differences, a key process in tubulogenesis is the development of cell polarity, the segregation of functionally distinct plasma membrane domains. Yet how tubules develop a single, continuous lumen with high fidelity is not well understood.Įpithelial tubules are one of the most common tissue types in metazoa, and there is remarkable diversity in the structure and mechanisms by which tubules develop ( Marciano, 2017 Iruela-Arispe and Beitel, 2013). Within each tubule, the presence of a continuous lumen is essential to its function: even a small discontinuity would block the passage of filtrate, thereby abolishing its excretory function. ![]() In the kidney, tubules have a single layer of epithelial cells surrounding a central lumen. The formation and elongation of epithelial tubules is a central feature of many organs. ![]() Together, these results support a model whereby afadin determines lumen placement by directing apical-basal spindle orientation, resulting in a continuous lumen and normal tubule morphogenesis. Absence of afadin in vivo leads to misorientation of apical-basal cell division in nephron tubules. However, cell division is oriented perpendicular to the apical-basal axis. Unexpectedly, in vivo examination of early-stage developing nephron tubules reveals that cell division is not oriented in the longitudinal (or planar-polarized) axis. In tubules, cell division may be oriented relative to two axes: longitudinal and apical-basal. Using an in vitro 3D cyst model, we find that afadin localizes to the cell cortex adjacent to the spindle poles and orients the mitotic spindle. Here, we demonstrate that afadin is required for lumen continuity by orienting the mitotic spindle during cell division. ![]() We recently found that the F-actin-binding protein afadin is required for lumen continuity in developing renal tubules, though its mechanism of action remains unknown. In many types of tubules, continuity of the lumen is paramount to tubular function, yet how tubules generate lumen continuity in vivo is not known.
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