Neddylation regulates the development and function of excitatory neurons
The development and function of neurons is orchestrated by a plethora of regulatory mechanisms that control the abundance, localization, interactions, and function of pro-teins. A key role in this regard is assumed by post-translational protein modifications (PTMs). While some PTM types, such as phosphorylation or ubiquitination, have been explored comprehensively, PTMs involving ubiquitin-like modifiers (Ubls) have remained comparably enigmatic (Ubls). This is particularly true for the Ubl Nedd8 and its conjuga-tion to proteins, i.e. neddylation, in nerve cells. In the present study, we generated a con-ditional Nedd8 knock-out mouse line and examined the consequences of Nedd8-deletion in cultured postmitotic glutamatergic neurons. Our findings reveal that Nedd8-ablation in young glutamatergic neurons causes alterations in the expression of devel-opmental transcription factors that control neuronal differentiation, ultimately leading to defects in the development of a mature glutamatergic neuronal phenotype. Apparent manifestations of these defects include increased vGlut2 expression levels, reduced vGlut1 and endophilin 1 expression levels, reduced dendrite complexity, and increased transmitter release probability. Collectively, our results highlight a pivotal role for neddyla-tion in controlling the fate of glutamatergic neurons and excitatory synaptic transmission.