Cell-cycle-dependent TGFβ-BMP antagonism regulates neural tube closure by modulating tight junctions
Cell-cycle-dependent TGFβ-BMP antagonism regulates neural tube closure by modulating tight junctions
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DOI：
10.1242/jcs.179192
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发表时间：
2017-01-01
影响因子：
4
通讯作者：
Agarwala, Seema
中科院分区：
文献类型：
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作者：
Amarnath, Smita;Agarwala, Seema
许多器官是通过将扁平上皮细胞片内陷并卷入管中而形成的。神经板腹侧中线的内陷形成正中铰接点（MHP），这是抬高神经皱襞的事件，对于神经管闭合（NTC）至关重要。 MHP 的形成涉及细胞形状的动态时空调节，但如何实现这些调节尚不清楚。在这里，我们发现细胞周期依赖性 BMP 和 TGF β 拮抗作用通过动态调节顶端（PAR 复合物）和基底外侧（LGL）极性蛋白之间的相互作用来引发 MHP 形成。 TGF beta 和 BMP 激活受体 (r)-SMAD [磷酸化 SMAD2 或 SMAD3 (pSMAD2,3)，或磷酸化 SMAD1、SMAD5 或 SMAD8 (pSMAD1,5,8)] 经历细胞周期依赖性调节和沿神经板顶端基底轴的核胞质穿梭。细胞质中的非典型 TGF β 和 BMP 活性决定了 pSMAD2,3 或 pSMAD1,5,8 是否与紧密连接（PAR 复合物）或 LGL 相关，以及 MHP 处是否会发生细胞形状变化。因此，BMP和TGFβ与极性蛋白的相互作用通过调节r-SMAD对紧密连接的竞争和LGL对r-SMAD的隔离来动态调节MHP的形成。
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 TGF beta antagonism elicits MHP formation by dynamically regulating interactions between apical (PAR complex) and basolateral (LGL) polarity proteins. TGF beta 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 TGF beta 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 TGF beta with polarity proteins dynamically modulate MHP formation by regulating r-SMAD competition for tight junctions and r-SMAD sequestration by LGL.