Epithelial relaxation mediated by the myosin phosphatase regulator Mypt1 is required for brain ventricle lumen expansion and hindbrain morphogenesis
Epithelial relaxation mediated by the myosin phosphatase regulator Mypt1 is required for brain ventricle lumen expansion and hindbrain morphogenesis
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DOI：
10.1242/dev.042705
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发表时间：
2010-03-01
期刊：
影响因子：
4.6
通讯作者：
Sive, Hazel
中科院分区：
文献类型：
--
作者：
Gutzman, Jennifer H.;Sive, Hazel
我们证明，在斑马鱼后脑中，细胞形状、菱形形态发生以及出人意料的脑室管腔扩张取决于神经上皮的收缩状态。后脑神经管以特定的顺序打开，最初沿着菱形边界的中线分离，随后在菱形内开口，最终开口合并到后脑室腔中。肌球蛋白磷酸酶调节剂 mypt1 发生突变，由于周围神经上皮的伸展受损，导致心室变小。尽管最初的后脑开口保持正常，但 mypt1 突变菱形体不会经历正常的形态进展。三维重建表明，在 mypt1 突变体中菱粒内和菱粒边界处的细胞形状异常。野生型细胞形状要求周围细胞也是野生型，而突变型细胞形状是自主调节的。野生型胚胎显示出动态水平的磷酸化肌球蛋白调节轻链（pMRLC），支持后脑形态发生过程中肌球蛋白功能调节的要求。相比之下，突变体表现出持续高的 pMRLC 水平，pMRLC 和肌球蛋白 II 浓度在上皮的顶端侧，肌球蛋白 II 和肌动蛋白浓度在菱形边界处。抑制肌球蛋白 II 功能可挽救脑室管腔扩张、菱形形态和细胞形状，这表明每种缺陷都是肌球蛋白过度活跃的结果。我们认为上皮必须通过肌球蛋白磷酸酶的活性“松弛”，以允许正常的后脑形态发生和脑室腔的扩张。上皮松弛可能是促进许多器官管膨胀的一种广泛策略。
We demonstrate that in the zebrafish hindbrain, cell shape, rhombomere morphogenesis and, unexpectedly, brain ventricle lumen expansion depend on the contractile state of the neuroepithelium. The hindbrain neural tube opens in a specific sequence, with initial separation along the midline at rhombomere boundaries, subsequent openings within rhombomeres and eventual coalescence of openings into the hindbrain ventricle lumen. A mutation in the myosin phosphatase regulator mypt1 results in a small ventricle due to impaired stretching of the surrounding neuroepithelium. Although initial hindbrain opening remains normal, mypt1 mutant rhombomeres do not undergo normal morphological progression. Three-dimensional reconstruction demonstrates cell shapes within rhombomeres and at rhombomere boundaries are abnormal in mypt1 mutants. Wild-type cell shape requires that surrounding cells are also wild type, whereas mutant cell shape is autonomously regulated. Supporting the requirement for regulation of myosin function during hindbrain morphogenesis, wild-type embryos show dynamic levels of phosphorylated myosin regulatory light chain (pMRLC). By contrast, mutants show continuously high pMRLC levels, with concentration of pMRLC and myosin II at the apical side of the epithelium, and myosin II and actin concentration at rhombomere boundaries. Brain ventricle lumen expansion, rhombomere morphology and cell shape are rescued by inhibition of myosin II function, indicating that each defect is a consequence of overactive myosin. We suggest that the epithelium must 'relax', via activity of myosin phosphatase, to allow for normal hindbrain morphogenesis and expansion of the brain ventricular lumen. Epithelial relaxation might be a widespread strategy to facilitate tube inflation in many organs.