A novel mouse model for inhibition of DOHH-mediated hypusine modification reveals a crucial function in embryonic development, proliferation and oncogenic transformation.

The central importance of translational control by post-translational modification has spurred major interest in regulatory pathways that control translation. One such pathway uniquely adds hypusine to eukaryotic initiation factor 5A (eIF5A), and thereby affects protein synthesis and, subsequently, cellular proliferation through an unknown mechanism. Using a novel conditional knockout mouse model and a Caenorhabditis elegans knockout model, we found an evolutionarily conserved role for the DOHH-mediated second step of hypusine synthesis in early embryonic development. At the cellular level, we observed reduced proliferation and induction of senescence in 3T3 Dohh-/- cells as well as reduced capability for malignant transformation. Furthermore, mass spectrometry showed that deletion of DOHH results in an unexpected complete loss of hypusine modification. Our results provide new biological insight into the physiological roles of the second step of the hypusination of eIF5A. Moreover, the conditional mouse model presented here provides a powerful tool for manipulating hypusine modification in a temporal and spatial manner, to analyse both how this unique modification normally functions in vivo as well as how it contributes to different pathological conditions.

Cholinergic control in developing prefrontal-hippocampal networks.

The cholinergic drive enhances input processing in attentional and mnemonic context by interacting with the activity of prefrontal-hippocampal networks. During development, acetylcholine modulates neuronal proliferation, differentiation, and synaptic plasticity, yet its contribution to the maturation of cognitive processing resulting from early entrainment of neuronal networks in oscillatory rhythms remains widely unknown. Here we show that cholinergic projections growing into the rat prefrontal cortex (PFC) toward the end of the first postnatal week boost the generation of nested gamma oscillations superimposed on discontinuous spindle bursts by acting on functional muscarinic but not nicotinic receptors. Although electrical stimulation of cholinergic nuclei increased the occurrence of nested gamma spindle bursts by 41%, diminishment of the cholinergic input by either blockade of the receptors or chronic immunotoxic lesion had the opposite effect. This activation of locally generated gamma episodes by direct cholinergic projections to the PFC was accompanied by indirect modulation of underlying spindle bursts via cholinergic control of hippocampal theta activity. With ongoing maturation and switch of network activity from discontinuous bursts to continuous theta-gamma rhythms, accumulating cholinergic projections acting on both muscarinic and nicotinic receptors mediated the transition from high-amplitude slow to low-amplitude fast rhythms in the PFC. By exerting multiple actions on the oscillatory entrainment of developing prefrontal-hippocampal networks, the cholinergic input may refine them for later gating processing in executive and mnemonic tasks.