Cell cycle dependent TGFβ-BMP antagonism regulates neural tube closure by modulating tight junctions

Abstract

Many organs form by invaginating and rolling flat epithelial cell-sheets into tubes. Invagination of the ventral midline of the neural plate forms the median hinge point (MHP), an event that elevates the neural folds and is essential for neural tube closure (NTC). MHP formation involves dynamic spatiotemporal modulations of cell shape, but how these are achieved is not understood. We show that cell cycle dependent BMP and TGFβ antagonism elicits MHP formation by dynamically regulating interactions between apical (PAR complex) and basolateral (LGL) polarity proteins. TGFβ and BMP activated receptor (r)-SMADs (pSMAD2,3, pSMAD1,5,8) undergo cell cycle dependent modulations and nucleo-cytosolic shuttling along the apicobasal axis of the neural plate. Non-canonical TGFβ and BMP activity in the cytosol determines whether pSMAD2,3 or pSMAD1,5,8 associates with the tight junction (PAR complex) or with LGL, and whether cell-shape changes can occur at the MHP. Thus BMP and TGFβ interactions with polarity proteins dynamically modulate MHP formation by regulating r-SMAD competition for tight junctions and r-SMAD sequestration by LGL.