title: 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. Here, 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 [phosphorylated SMAD2 or SMAD3 (pSMAD2,3), or phosphorylated SMAD1, SMAD5 or SMAD8 (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, the interactions of BMP and TGFβ with polarity proteins dynamically modulate MHP formation by regulating r-SMAD competition for tight junctions and r-SMAD sequestration by LGL.
authors.affiliation: Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Smita
authors.initials: S
authors.lastname: Amarnath
authors.affiliation: Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA agarwala@austin.utexas.edu.|Institute for Cell and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.|Institute for Neuroscience, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Seema
authors.identifier: 0000-0002-6495-2962
authors.initials: S
authors.lastname: Agarwala
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002453:Cell Cycle; D019070:Cell Lineage; D002467:Cell Nucleus / Q000378:metabolism; D016764:Cell Polarity; D048430:Cell Shape; D002642:Chick Embryo; D008024:Ligands; D008954:Models, Biological; D054259:Neural Tube / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D008024:Ligands; D051785:Smad Proteins; D016212:Transforming Growth Factor beta
keywords: Apicobasal polarity; Hinge point; LGL; Midbrain; Neural tube closure defects; Organogenesis; PAR3