The differentiation and the development of neurons are strictly controlled by multiple signaling pathways such as protein and lipid phosphorylation, GTP hydrolysis, and Ca2+ signaling, which often crosstalk and interfere each other. Among numerous signaling mechanisms, the most well-known example is phosphatase and tensin homolog (PTEN). PTEN is a lipid phosphatase that converts phosphatidylinositol-3,4,5-trisphosphate (PtdInsP3) into phosphatidylinositol-4,5-bisphosphate (PtdInsP2) and counteracts phosphoinositide-3-kinase-dependent (PI3K-dependent) signaling. PTEN plays diverse roles in neuronal development in multiple developmental stages. Recent emerging evidence shows that ubiquitination also plays crucial roles in neurogenesis, migration of the neurons, neurite development, and synaptogenesis. Previous studies by other groups indicated that the Nedd4 family E3 ubiquitin ligases Nedd4-1 and Nedd4-2 ubiquitinate PTEN, leading it for proteasomal degradation, and thereby regulate axonal growth in developing neurons. Indeed, in several types of cells, functions of PTEN and Nedd4 E3 ligases are totally opposed. Using conditional knock-out mice, we show here that Nedd4-1 and Nedd4-2 are indeed required for axonal growth in murine central nervous system neurons in the in vitro primary culture system and in vivo. In my presentation, I will explain the functional relationship between PTEN and Nedd4 E3 ligases using genetical, cell biological, and biochemical approaches.