Loss of Llgl1 in retinal neuroepithelia reveals links between apical domain size, Notch activity and neurogenesis
Loss of Llgl1 in retinal neuroepithelia reveals links between apical domain size, Notch activity and neurogenesis
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DOI：
10.1242/dev.078097
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发表时间：
2012-05-01
期刊：
影响因子：
4.6
通讯作者：
Link, Brian A.
中科院分区：
文献类型：
--
作者：
Clark, Brian S.;Cui, Shuang;Link, Brian A.
为了深入了解神经发生的细胞机制，我们分析了视网膜神经上皮细胞缺乏Llgl 1，一种涉及顶基底细胞极性，不对称细胞分裂，细胞形状和细胞周期退出的蛋白质。我们发现，脊椎动物视网膜神经上皮细胞缺乏Llgl 1保留明显的apicobasal极性，但扩大了顶端域。Llgl 1视网膜祖细胞也具有增加的Notch活性和降低的神经发生率。通过消耗Rbpj阻断Notch功能恢复了正常的神经发生。通过抑制Shroom 3，顶端结构域的实验性扩张也增加了Notch活性并减少了神经发生。值得注意的是，在野生型视网膜中，神经源性视网膜祖细胞与增殖性神经上皮细胞相比具有较小的顶端结构域。由于核在运动间核迁移（IKNM）的位置已经与细胞周期退出，我们分析了这种现象，在细胞耗尽Llgl 1。我们发现，虽然IKNM是正常的，核位置和神经发生之间的关系被转移远离顶端表面，与增加的促增殖和/或抗神经源性信号与顶端域相一致。这些数据，结合其他研究结果，表明，在视网膜神经上皮细胞，顶端域的大小调制影响神经发生的极化信号的强度。
To gain insights into the cellular mechanisms of neurogenesis, we analyzed retinal neuroepithelia deficient for Llgl1, a protein implicated in apicobasal cell polarity, asymmetric cell division, cell shape and cell cycle exit. We found that vertebrate retinal neuroepithelia deficient for Llgl1 retained overt apicobasal polarity, but had expanded apical domains. Llgl1 retinal progenitors also had increased Notch activity and reduced rates of neurogenesis. Blocking Notch function by depleting Rbpj restored normal neurogenesis. Experimental expansion of the apical domain, through inhibition of Shroom3, also increased Notch activity and reduced neurogenesis. Significantly, in wild-type retina, neurogenic retinal progenitors had smaller apical domains compared with proliferative neuroepithelia. As nuclear position during interkinetic nuclear migration ( IKNM) has been previously linked with cell cycle exit, we analyzed this phenomenon in cells depleted of Llgl1. We found that although IKNM was normal, the relationship between nuclear position and neurogenesis was shifted away from the apical surface, consistent with increased pro-proliferative and/or anti-neurogenic signals associated with the apical domain. These data, in conjunction with other findings, suggest that, in retinal neuroepithelia, the size of the apical domain modulates the strength of polarized signals that influence neurogenesis.