Stegmüller Judith, Konishi Yoshiyuki, Huynh Mai Anh, Yuan Zengqiang, Dibacco Sara, Bonni Azad
Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
Neuron. 2006 May 4;50(3):389-400. doi: 10.1016/j.neuron.2006.03.034.
Axonal growth is fundamental to the establishment of neuronal connectivity in the brain. However, the cell-intrinsic mechanisms that govern axonal morphogenesis remain to be elucidated. The ubiquitin ligase Cdh1-anaphase-promoting complex (Cdh1-APC) suppresses the growth of axons in postmitotic neurons. Here, we report that Cdh1-APC operates in the nucleus to inhibit axonal growth. We also identify the transcriptional corepressor SnoN as a key target of neuronal Cdh1-APC that promotes axonal growth. Cdh1 forms a physical complex with SnoN and stimulates the ubiquitin-dependent proteasomal degradation of SnoN in neurons. Knockdown of SnoN in neurons significantly reduces axonal growth and suppresses Cdh1 RNAi enhancement of axonal growth. In addition, SnoN knockdown in vivo suggests an essential function for SnoN in the development of granule neuron parallel fibers in the cerebellar cortex. These findings define Cdh1-APC and SnoN as components of a cell-intrinsic pathway that orchestrates axonal morphogenesis in a transcription-dependent manner in the mammalian brain.
轴突生长是大脑中神经元连接建立的基础。然而，控制轴突形态发生的细胞内在机制仍有待阐明。泛素连接酶Cdh1-后期促进复合体（Cdh1-APC）抑制有丝分裂后神经元的轴突生长。在此，我们报告Cdh1-APC在细胞核中发挥作用以抑制轴突生长。我们还确定转录共抑制因子SnoN是促进轴突生长的神经元Cdh1-APC的关键靶点。Cdh1与SnoN形成物理复合物，并刺激神经元中SnoN的泛素依赖性蛋白酶体降解。神经元中SnoN的敲低显著降低轴突生长，并抑制Cdh1 RNA干扰对轴突生长的增强作用。此外，体内SnoN敲低表明SnoN在小脑皮质颗粒神经元平行纤维发育中具有重要功能。这些发现将Cdh1-APC和SnoN定义为哺乳动物大脑中以转录依赖方式协调轴突形态发生的细胞内在途径的组成部分。
