Mingorance-Le Meur Ana, O'Connor Timothy P
Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
EMBO J. 2009 Feb 4;28(3):248-60. doi: 10.1038/emboj.2008.265. Epub 2008 Dec 18.
During development, neurons extend projections that pathfind to reach their appropriate targets. These projections are composed of two distinct domains: a highly dynamic growth cone and a stable neurite shaft, which is considered to be consolidated. Although the regulation of these domains is critical to the appropriate formation of neural networks, the molecular mechanisms that regulate neurite shape remain poorly understood. Here, we show that calpain protease activity localizes to the neurite shaft, where it is essential for the repression of protrusive activity by limiting cortactin levels and inhibiting actin polymerization. Correspondingly, inhibition of calpain by branching factors induces the formation of new growth cones along the neurite shaft through cAMP elevation. These findings demonstrate that neurite consolidation is an active process requiring constant repression of protrusive activity. We also show that sprouting is, at least in part, accomplished by turning off the mechanism of consolidation.
在发育过程中，神经元会延伸突起，这些突起通过路径寻找到达其合适的靶标。这些突起由两个不同的区域组成：一个高度动态的生长锥和一个稳定的神经突轴，后者被认为是已巩固的。尽管这些区域的调节对于神经网络的适当形成至关重要，但调节神经突形状的分子机制仍知之甚少。在这里，我们表明钙蛋白酶活性定位于神经突轴，在那里它通过限制皮层肌动蛋白水平和抑制肌动蛋白聚合来抑制突出活动，这一点至关重要。相应地，通过分支因子抑制钙蛋白酶会通过提高cAMP沿着神经突轴诱导新生长锥的形成。这些发现表明神经突巩固是一个活跃的过程，需要不断抑制突出活动。我们还表明，发芽至少部分是通过关闭巩固机制来完成的。
