Developmental roles for Srf, cortical cytoskeleton and cell shape in epidermal spindle orientation.
Developmental roles for Srf, cortical cytoskeleton and cell shape in epidermal spindle orientation.
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DOI：
10.1038/ncb2163
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发表时间：
2011-03
影响因子：
21.3
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中科院分区：
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在发育过程中，极化的表皮层经历分层和分化，形成皮肤屏障。该过程涉及肌动蛋白动力学、纺锤体重定向和Notch信号，其机制尚不清楚。为了阐明表皮胚胎发生是如何调控的，我们有条件地靶向血清反应因子（Srf），这是一种对表皮分化至关重要的转录因子。出乎意料的是，先前认为的致病缺陷并不是造成胚胎表皮严重紊乱的原因。为了寻找这一机制，我们确定了消融术后下调的肌动蛋白及其调节因子。没有Srf，细胞表现出皮质网络减少，在有丝分裂中，它们不能聚集，我们在体内用低剂量的肌动蛋白抑制剂和体外shrna敲低来概括这些特征。同时，ERM和皮质肌球蛋白iia的磷酸化也发生了改变，在体外实验中显示，这可以建立一个刚性的皮质肌动球蛋白网络，并引发关键的形状变化。我们提供了这些特征与Srf损失之间的联系，并且我们表明该过程在皮肤中具有生理学相关性，反映在纺锤体取向缺陷，不对称细胞分裂，分层和分化上。
During development, a polarized epidermal sheet undergoes stratification and differentiation to produce the skin barrier. Through mechanisms that are poorly understood, the process involves actin dynamics, spindle reorientation and Notch signalling. To elucidate how epidermal embryogenesis is governed, we conditionally targeted serum response factor (Srf), a transcription factor that is essential for epidermal differentiation. Unexpectedly, previously ascribed causative defects are not responsible for profoundly perturbed embryonic epidermis. Seeking the mechanism for this, we identified actins and their regulators that were downregulated after ablation. Without Srf, cells exhibit a diminished cortical network and in mitosis, they fail to round up, features we recapitulate with low-dose actin inhibitors in vivo and shRNA-knockdown in vitro. Altered concomitantly are phosphorylated ERM and cortical myosin-IIA, shown in vitro to establish a rigid cortical actomyosin network and elicit critical shape changes. We provide a link between these features and Srf loss, and we show that the process is physiologically relevant in skin, as reflected by defects in spindle orientation, asymmetric cell divisions, stratification and differentiation.