Ikeuchi Yoshiho, Stegmüller Judith, Netherton Stuart, Huynh Mai Anh, Masu Masayuki, Frank David, Bonni Shirin, Bonni Azad
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Neurosci. 2009 Apr 1;29(13):4312-21. doi: 10.1523/JNEUROSCI.0126-09.2009.
The transcriptional corepressor SnoN is a critical regulator of axonal morphogenesis, but how SnoN drives axonal growth is unknown. Here, we report that gene-profiling analyses in cerebellar granule neurons reveal that the large majority of genes altered upon SnoN knockdown are surprisingly downregulated, suggesting that SnoN may activate transcription in neurons. Accordingly, we find that the transcriptional coactivator p300 interacts with SnoN, and p300 plays a critical role in SnoN-induced axon growth. We also identify the gene encoding the signaling scaffold protein Ccd1 as a critical target of SnoN in neurons. Ccd1 localizes to the actin cytoskeleton, is enriched at axon terminals in neurons, and activates the axon growth-promoting kinase JNK (c-Jun N-terminal protein kinase). Knockdown of Ccd1 in neurons reduces axonal length and suppresses the ability of SnoN to promote axonal growth. Importantly, Ccd1 knockdown in rat pups profoundly impairs the formation of granule neuron parallel fiber axons in the rat cerebellar cortex in vivo. These findings define a novel SnoN-Ccd1 link that promotes axonal growth in the mammalian brain, with important implications for axonal development and regeneration.
转录共抑制因子SnoN是轴突形态发生的关键调节因子，但SnoN如何驱动轴突生长尚不清楚。在此，我们报告，对小脑颗粒神经元进行的基因谱分析显示，在敲低SnoN后，绝大多数发生改变的基因令人惊讶地被下调，这表明SnoN可能在神经元中激活转录。相应地，我们发现转录共激活因子p300与SnoN相互作用，并且p300在SnoN诱导的轴突生长中起关键作用。我们还确定编码信号支架蛋白Ccd1的基因是SnoN在神经元中的关键靶点。Ccd1定位于肌动蛋白细胞骨架，在神经元的轴突末端富集，并激活促进轴突生长的激酶JNK（c-Jun氨基末端蛋白激酶）。敲低神经元中的Ccd1会缩短轴突长度，并抑制SnoN促进轴突生长的能力。重要的是，敲低大鼠幼崽中的Ccd1会严重损害体内大鼠小脑皮质中颗粒神经元平行纤维轴突的形成。这些发现确定了一种新的SnoN-Ccd1联系，该联系促进哺乳动物大脑中的轴突生长，对轴突发育和再生具有重要意义。
