You have full access to this open access article. Circuit formation in the nervous system essentially relies on the proper development of neurons and their processes. In this context, the ubiquitin ligase Nedd4 is a crucial modulator of axonal and dendritic branching. Herein we characterize the Nedd4-binding protein 3 N4BP3 , a Fezzin family member, during nerve cell development. In developing rat primary hippocampal neurons, endogenous N4BP3 localizes to neuronal processes, including axons and dendrites.
Transient in vitro knockdown of N4BP3 in hippocampal cultures during neuritogenesis results in impaired branching of axons and dendrites. In line with these findings, in vivo knockdown of n4bp3 in Xenopus laevis embryos results in severe alteration of cranial nerve branching.
We introduce N4BP3 as a novel molecular element for the correct branching of neurites in developing neurons and propose a central role for an N4BP3-Nedd4 complex in neurite branching and circuit formation.
Depending on the pattern and extent of how axons and dendrites undergo branching, a neuron has the ability to regulate the level of wiring and the strength of synaptic circuits. In this context, the ubiquitin proteasome system UPS has emerged as a decisive regulatory pathway[ 1 β 12 ]. Accumulating data underline the fact that Nedd4 neural precursor cell expressed and developmentally downregulated , a HECT homologous to E6-AP carboxyl terminus domain ubiquitin ligase[ 13 ], is of special importance for neuronal network formation because of its capacity to regulate the growth and arborization of both dendrites and axons[ 14 β 18 ].
In the murine brain, for example, Nedd4 turns down Ras-related protein 2A Rap2A function, thus inhibiting Rap2 effector kinases of the Traf2- and Nck-interacting kinase TINK family and thereby promoting dendritic growth and arborization[ 16 ]. Nedd4 was further shown to promote phosphatidylinositol 3-kinase PI3K -induced cytoskeletal rearrangements via UPS-mediated downregulation of the Nedd4 substrate phosphatase and tensin homolog PTEN to generate a terminally branched arbor in axons of Xenopus laevis retinal ganglion cells RGCs [ 15 ].
