Developing renal tubules orient cell division via Afadin to position the tubule lumen [RESEARCH ARTICLE]

Lei Gao, Zhufeng Yang, Chitkale Hiremath, Susan E. Zimmerman, Blake Long, Paul R. Brakeman, Keith E. Mostov, David M. Bryant, Katherine Luby-Phelps, and Denise K. Marciano

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. We recently found the F-actin binding protein Afadin is required for lumen continuity in developing renal tubules, though its mechanism of action remains unknown. Here we demonstrate Afadin is required for lumen continuity by orienting the mitotic spindle during cell division. Using an in vitro 3D cyst model, we find Afadin localizes to the cell cortex adjacent to the spindle poles and orients the mitotic spindle. In tubules, cell division may be oriented relative to two axes, longitudinal and apical-basal. Unexpectedly, in vivo examination of early stage developing nephron tubules reveals cell division is not oriented in the longitudinal (or planar polarized) axis. However, cell division is oriented perpendicular to the apical-basal axis. Absence of Afadin in vivo leads to misorientation of apical-basal cell division in nephron tubules. Together these results support a model whereby Afadin determines lumen placement by directing apical-basal spindle orientation, which generates a continuous lumen and normal tubule morphogenesis.

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