Bone morphogenetic proteins regulate hinge point formation during neural tube closure by dynamic modulation of apicobasal polarity

摘要

BACKGROUND: A critical event in neural tube closure is the formation of median hinge points (MHPs) and dorsolateral hinge points (DLHPs). Together, they buckle the ventral midline and elevate and juxtapose the neural folds for proper neural tube closure. Dynamic cell behaviors occur at hinge points (HPs), but their molecular regulation is largely unexplored. Bone morphogenetic proteins (BMPs) have been implicated in a variety of neural tube closure defects, although the underlying mechanisms are poorly understood. METHODS: In this study, we used in vivo electroporations, high-resolution microscopy, and biochemical analyses to explore the role of BMP signaling in chick midbrain neural tube closure. RESULTS: We identified a cell-cycle-dependent BMP gradient in the midbrain neural plate, which results in low-level BMP activity at the MHP. We show that although BMP signaling does not have a role in midbrain cell-fate specification, its attenuation is necessary and sufficient for MHP formation and midbrain closure. BMP blockade induces MHP formation by regulating apical constriction and basal nuclear migration. Furthermore, BMP signaling is critically important for maintaining epithelial organization by biochemically interacting with apicobasal polarity proteins (e.g., PAR3). As a result, prolonged BMP blockade disrupts apical junctions, desegregating the apical (PAR3 +, ZO1 +) and basolateral (LGL +) compartments. Direct apical LGL-GFP misexpression in turn is sufficient to induce ectopic HPs. CONCLUSIONS: BMPs have a critical role in maintaining epithelial organization, a role that is conserved across species and tissue types. Its cell-cycle-dependent modulation in the neural plate dynamically regulates apicobasal polarity and helps to bend, shape, and close the neural tube. Birth Defects Research (Part A) 2012.