Neuron specific ablation of eIF5A or deoxyhypusine synthase leads to impairment in development and cognitive functions in mice

Abstract

Eukaryotic initiation factor 5A (eIF5A) is an essential factor with a unique amino acid, hypusine, required for its activity. Hypusine is formed exclusively in eIF5A by a post-translational modification involving two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Each of the three genes, Eif5a, Dhps or 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 have generated four conditional knockout mouse strains using the Emx1-Cre or Camk2a-Cre strain 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 (E.9.5, 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 hippocampus) did not lead to global developmental defects; rather, these knockout animals exhibited severe impairment in spatial learning, contextual learning and memory, when subjected to the Morris Water Maze test and a contextual learning test. In both models, the Dhps knockout mice displayed more severe impairment than their Eif5a knockout counterparts. The observed defects in 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. SignificanceeIF5A, an essential translation factor, is the only protein that undergoes a unique posttranslational modification, that converts lysine to hypusine by conjugation of the aminobutyl moiety from the polyamine spermidine. Hypusine biosynthesis occurs by two enzymatic steps involving deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Mutations in EIF5A or DHPS have been associated with rare neurodevelopmental disorders in humans. To understand the mechanisms underlying the pathogenesis of the disease, we generated mutant mice with brain-specific deletions of Eif5a or Dhps. The Eif5a and Dhps conditional knockout mice exhibited impairment in brain development, growth and cognitive functions. These animal models may serve as useful tools in the development of therapies against the eIF5A- or DHPS-associated neurodevelopmental disorders.