Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel.
Neuron. 2016 Dec 7;92(5):991-1006. doi: 10.1016/j.neuron.2016.10.061. Epub 2016 Nov 23.
Developmental neuronal cell death and axonal elimination are controlled by transcriptional programs, of which their nature and the function of their components remain elusive. Here, we identified the dual specificity phosphatase Dusp16 as part of trophic deprivation-induced transcriptome in sensory neurons. Ablation of Dusp16 enhanced axonal degeneration in response to trophic withdrawal, suggesting that it has a protective function. Moreover, axonal skin innervation was severely reduced while neuronal elimination was increased in the Dusp16 knockout. Mechanistically, Dusp16 negatively regulates the transcription factor p53 and antagonizes the expression of the pro-degenerative factor, Puma (p53 upregulated modulator of apoptosis). Co-ablation of Puma with Dusp16 protected axons from rapid degeneration and specifically reversed axonal innervation loss early in development with no effect on neuronal deficits. Overall, these results reveal that physiological axonal elimination is regulated by a transcriptional program that integrates regressive and progressive elements and identify Dusp16 as a new axonal preserving factor.
发育中的神经元细胞死亡和轴突消除受转录程序控制，但其性质及其组成部分的功能仍难以捉摸。在这里，我们确定了双特异性磷酸酶 Dusp16 是感觉神经元中营养剥夺诱导的转录组的一部分。Dusp16 的缺失增强了对营养剥夺的轴突退化反应，表明它具有保护功能。此外，Dusp16 基因敲除小鼠的皮肤感觉神经支配严重减少，而神经元消除增加。从机制上讲，Dusp16 负调控转录因子 p53，并拮抗促退化因子 Puma（p53 上调凋亡调节因子）的表达。Puma 与 Dusp16 的共同缺失可保护轴突免受快速退化，并且特异性地逆转发育早期的轴突神经支配丧失，而对神经元缺陷没有影响。总的来说，这些结果表明，生理轴突消除受转录程序调控，该程序整合了退行性和进行性因素，并确定 Dusp16 为一种新的轴突保护因子。
