In the advance of mammalian axonal growth cones, adherent

L1 can provide the tracking force for growth cone extension (Kamiguchi, 2003). As the growth cone advances, L1 is endocytosed in the central region to release unnecessary adhesion and recycled back to the peripheral region. Similarly, continuously recycling of Nrg along the dendritic XAV939 membrane may help its delivery to growing dendrites that potentially function in promoting dendrite extension or stabilizing newly formed dendrites. Excessive Nrg in higher-order dendrites as in da neurons overexpressing Nrg may inhibit dendrite arborization by generating superfluous adhesion. Thus, Nak-mediated endocytosis could alleviate this inhibition by internalizing signaling pathway Nrg from the cell surface, allowing dendrite elongation. Arborization of higher-order dendrites in Drosophila da neurons

requires branching out new dendrites and elongation of existing ones, which requires two other cellular machineries. First, transporting the branch-promoting Rab5-positive organelles to distal dendrites by the microtubule-based dynein transport system is essential for branching activity ( Satoh et al., 2008 and Zheng et al., 2008b). In the absence of Rab5 activity, dendritic branching is largely eliminated, and lacking the dynein transport activity limits branching activity to proximal dendrites. Second, the satellite secretory pathway

contributes to dendrite growth by mobilizing Golgi outposts to protruding dendrites ( Ye et al., 2007). Similar to Rab proteins, the Golgi outposts labeled by ManII-GFP were only partially colocalized with YFP-Nak ( Figure S5J), and their dendritic distribution is independent of Nak MTMR9 activity ( Figure 5I). Also, in lva-RNAi larvae in which the transport of Golgi outposts is disrupted ( Ye et al., 2007), YFP-Nak puncta were localized normally to distal dendrites ( Figure S5D). These findings suggest that localization of Golgi outposts in dendrites is not dependent on Nak activity, and localization of YFP-Nak is not dependent on transport of Golgi outposts. We envision that arborization of dendrites is achieved by transporting the branch-promoting factors like Rab5 distally via the dynein transport system. Following the initiation of new branches, dendrite extension requires growth-promoting activity provided by the anterograde Golgi outposts and localized clathrin puncta to promote local growth. To actively distribute clathrin puncta in distal dendrites that are far away from the soma, Nak can participate in the condensation of efficient endocytosis into the punctate structures in higher-order dendrites.