Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice

Rajesh Kumar Kar,Ashleigh S Hanner,Matthew F Starost,Danielle Springer,Teresa L Mastracci,Raghavendra G Mirmira,Myung Hee Park

doi:10.1016/j.jbc.2021.101333

Abstract

Eukaryotic initiation factor 5A (eIF5A)†, ‡ is an essential protein that requires a unique amino acid, hypusine, for its activity. Hypusine is formed exclusively in eIF5A post-translationally via two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase. Each of the genes encoding these proteins, Eif5a, Dhps, and Dohh, is required for mouse embryonic development. Variants in EIF5A or DHPS were recently identified as the genetic basis underlying certain rare neurodevelopmental disorders in humans. To investigate the roles of eIF5A and DHPS in brain development, we generated four conditional KO mouse strains using the Emx1-Cre or Camk2a-Cre strains and examined the effects of temporal- and region-specific deletion of Eif5a or Dhps. The conditional deletion of Dhps or Eif5a by Emx1 promotor–driven Cre expression (E9.5, in the cortex and hippocampus) led to gross defects in forebrain development, reduced growth, and premature death. On the other hand, the conditional deletion of Dhps or Eif5a by Camk2a promoter–driven Cre expression (postnatal, mainly in the CA1 region of the hippocampus) did not lead to global developmental defects; rather, these KO animals exhibited severe impairment in spatial learning, contextual learning, and memory when subjected to the Morris water maze and a contextual learning test. In both models, the Dhps-KO mice displayed more severe impairment than their Eif5a-KO counterparts. The observed defects in the brain, global development, or cognitive functions most likely result from translation errors due to a deficiency in active, hypusinated eIF5A. Our study underscores the important roles of eIF5A and DHPS in neurodevelopment.

Highlights

Our Eukaryotic initiation factor 5A (eIF5A) and deoxyhypusine synthase (DHPS) in brain development, we study underscores the important roles of eIF5A
P the CKO strains do not harbor the same - variants of the EIF5A and the DHPS genes as e those of the affected human individuals, it is r interesting to note that certain features of the P human neurodevelopmental disorders, l including intellectual disability, developmental delay, reduced growth, and shortened lifespan, a are reflected in the phenotypes of these CKO n mice
R The deletion of Eif5a or Dhps in the u Emx1-expressing neurons from the mido embryonic stage resulted in gross J morphological abnormalities in brain; cerebral underlying the loss of cortex and hippocampus may involve the failure of neural stem cells to proliferate or to differentiate, apoptosis of differentiating cells, or a failure of differentiating cells to proliferate

Summary

Introduction

Re Results l P Generation of four conditional knockout strains: Eif5a fl/fl;Emx1-Cre (Eif5aEmx), Dhps a fl/fl;Emx1-Cre (DhpsEmx), Eif5afl/fl;Camk2an Cre (Eif5aCamk2a) and Dhpsfl/fl;Camk2a-Cre r (DhpsCamk2a) The effects of deletion of Dhps or Eif5a on cerebral cortex and hippocampus at 4 months brain development and morphology (Fig. 6, G and K).

Results

Conclusion