Hammond Vicki E, Gunnersen Jenny M, Goh Choo-Peng, Low Ley-Hian, Hyakumura Tomoko, Tang Michelle M, Britto Joanne M, Putz Ulrich, Howitt Jason A, Tan Seong-Seng
Florey Institute of Neuroscience and Mental Health and.
Florey Institute of Neuroscience and Mental Health and Department of Anatomy and Neuroscience, The University of Melbourne, Victoria 3010, Australia.
Cereb Cortex. 2014 Dec;24(12):3289-300. doi: 10.1093/cercor/bht191. Epub 2013 Jul 29.
Ubiquitin ligases of the Nedd4 family are important for axon and dendrite development, but little is known about their adaptor, Nedd4 family-interacting protein 1 (Ndfip1), that is responsible for their enzymatic activation. To study the function of Ndfip1 in cortical development, we generated a conditional knock-out (conditional KO) in neurons. The Ndfip1 conditional KO mice were viable; however, cortical neurons in the adult brain exhibited atrophic characteristics, including stunted dendritic arbors, blebbing of dendrites, and fewer dendritic spines. In electron micrographs, these neurons appeared shrunken with compacted somata and involutions of the nuclear membrane. In culture, Ndfip1 KO neurons exhibited exuberant sprouting suggesting loss of developmental control. Biochemical analysis of postsynaptic density (PSD) fractions from Ndfip1 KO cortical and hippocampal neurons showed that the postsynaptic proteins (Arc and PSD-95) were reduced compared with wild-type controls. In addition, the PI3 kinase/Akt signaling pathway was altered. These results indicate that Ndfip1, through its Nedd4 effectors, is important for the development of dendrites and dendritic spines in the cortex.
Nedd4家族的泛素连接酶对轴突和树突的发育很重要，但对其负责酶激活的衔接蛋白Nedd4家族相互作用蛋白1（Ndfip1）却知之甚少。为了研究Ndfip1在皮层发育中的功能，我们构建了神经元条件性敲除（条件性KO）小鼠。Ndfip1条件性KO小鼠可存活；然而，成年大脑中的皮层神经元表现出萎缩特征，包括树突分支发育不良、树突起泡和树突棘减少。在电子显微镜照片中，这些神经元看起来萎缩，胞体致密，核膜内陷。在培养中，Ndfip1 KO神经元表现出旺盛的发芽，表明发育控制丧失。对Ndfip1 KO皮层和海马神经元的突触后致密物（PSD）组分进行生化分析表明，与野生型对照相比，突触后蛋白（Arc和PSD-95）减少。此外，PI3激酶/Akt信号通路发生改变。这些结果表明，Ndfip1通过其Nedd4效应器，对皮层中树突和树突棘的发育很重要。
