Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
Cell Rep. 2013 Apr 25;3(4):971-7. doi: 10.1016/j.celrep.2013.03.005. Epub 2013 Apr 4.
Extensive axonal pruning and neuronal cell death are critical events for the development of the nervous system. Like neuronal cell death, axonal elimination occurs in discrete steps; however, the regulators of these processes remain mostly elusive. Here, we identify the kinesin superfamily protein 2A (KIF2A) as a key executor of microtubule disassembly and axonal breakdown during axonal pruning. Knockdown of Kif2a, but not other microtubule depolymerization or severing proteins, protects axonal microtubules from disassembly upon trophic deprivation. We further confirmed and extended this result to demonstrate that the entire degeneration process is delayed in neurons from the Kif2a knockout mice. Finally, we show that the Kif2a-null mice exhibit normal sensory axon patterning early during development, but abnormal target hyperinnervation later on, as they compete for limited skin-derived trophic support. Overall, these findings reveal a central regulatory mechanism of axonal pruning during development.
轴突广泛修剪和神经元细胞死亡是神经系统发育的关键事件。与神经元细胞死亡一样，轴突消除是分步骤发生的；然而，这些过程的调节剂在很大程度上仍难以捉摸。在这里，我们确定驱动蛋白超家族蛋白 2A（KIF2A）是轴突修剪过程中微管解聚和轴突断裂的关键执行者。击倒 Kif2a，但不是其他微管解聚或切断蛋白，可防止营养剥夺时轴突微管的解聚。我们进一步证实并扩展了这一结果，表明 Kif2a 基因敲除小鼠的神经元中的整个退化过程都被延迟。最后，我们表明，Kif2a 基因敲除小鼠在发育早期表现出正常的感觉轴突模式，但随后出现异常的靶组织过度神经支配，因为它们争夺有限的皮肤衍生的营养支持。总的来说，这些发现揭示了发育过程中轴突修剪的一个核心调节机制。
