Overexpression of PPK-1, the Caenorhabditis elegans Type I PIP kinase, inhibits growth cone collapse in the developing nervous system and causes axonal degeneration in adults.
Overexpression of PPK-1, the Caenorhabditis elegans Type I PIP kinase, inhibits growth cone collapse in the developing nervous system and causes axonal degeneration in adults.
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DOI：
10.1016/j.ydbio.2007.10.029
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发表时间：
2008
影响因子：
2.7
通讯作者：
D. Weinkove;M. Bastiani;Tamara A. M. Chessa;D. Joshi;Linda Hauth;F. Cooke;N. Divecha;K. Schuske
中科院分区：
文献类型：
--
作者：
D. Weinkove;M. Bastiani;Tamara A. M. Chessa;D. Joshi;Linda Hauth;F. Cooke;N. Divecha;K. Schuske
生长锥是动态膜结构，可根据环境提示重新排列细胞骨架，从而迁移至目标组织。脂质磷脂酰肌醇 (4,5) 二磷酸 (PIP2) 存在于所有真核细胞的质膜上，被认为是肌动蛋白细胞骨架重排所必需的。因此，PIP2 很可能在神经元发育过程中发挥作用，但这从未在体内进行过测试。在这项研究中，我们对秀丽隐杆线虫中的 PIP2 合成酶 I 型 PIP 激酶 (ppk-1) 进行了表征。 PPK-1 在神经系统中强烈表达，并且可以定位于质膜。我们表明，从秀丽隐杆线虫中纯化的 PPK-1 可以在体外产生 PIP2，并且该激酶的过度表达会导致体内 PIP2 水平增加。在发育中的神经元中，PPK-1 过度表达会导致生长锥停滞，产生异位膜投射和分支轴突。一旦神经元形成，PPK-1 过度表达会导致成年期细胞膜进行性过度生长和退化。这些数据表明，I 型 PIP 激酶的过度表达会抑制生长锥塌陷，并且调节已建立的神经元中的 PIP2 水平可能对于维持结构完整性和防止神经元变性很重要。
Growth cones are dynamic membrane structures that migrate to target tissue by rearranging their cytoskeleton in response to environmental cues. The lipid phosphatidylinositol (4,5) bisphosphate (PIP2) resides on the plasma membrane of all eukaryotic cells and is thought to be required for actin cytoskeleton rearrangements. Thus PIP2is likely to play a role during neuron development, but this has never been tested in vivo. In this study, we have characterized the PIP2synthesizing enzyme Type I PIP kinase (ppk-1) in Caenorhabditis elegans. PPK-1 is strongly expressed in the nervous system, and can localize to the plasma membrane. We show that PPK-1 purified from C. elegans can generate PIP2in vitro and that overexpression of the kinase causes an increase in PIP2levels in vivo. In developing neurons, PPK-1 overexpression leads to growth cones that become stalled, produce ectopic membrane projections, and branched axons. Once neurons are established, PPK-1 overexpression results in progressive membrane overgrowth and degeneration during adulthood. These data suggest that overexpression of the Type I PIP kinase inhibits growth cone collapse, and that regulation of PIP2levels in established neurons may be important to maintain structural integrity and prevent neuronal degeneration.