Essential role of eIF5A-1 and deoxyhypusine synthase in mouse embryonic development

Abstract

The eukaryotic initiation factor 5A (eIF5A) contains a polyamine-derived amino acid, hypusine [Nε-(4-amino-2-hydroxybutyl)lysine]. Hypusine is formed post-translationally by the addition of the 4-aminobutyl moiety from the polyamine spermidine to a specific lysine residue, catalyzed by deoxyhypusine synthase (DHPS), and by subsequent hydroxylation by deoxyhypusine hydroxylase (DOHH). The eIF5A precursor protein and both of its modifying enzymes are highly conserved, suggesting a vital cellular function for eIF5A and its hypusine modification. To address the functions of eIF5A and the first modification enzyme, DHPS, in mammalian development, we knocked out the Eif5a or the Dhps gene in mice. Eif5a heterozygous knockout mice and Dhps heterozygous knockout mice were viable and fertile. However, homozygous Eif5a1 gt/gt embryos and Dhps gt/gt embryos died early in embryonic development, between E3.5 and E7.5. Upon transfer to in vitro culture, homozygous Eif5a gt/gt or Dhps gt/gt blastocysts at E3.5 showed growth defects when compared to heterozygous or wild type blastocysts. Thus, the knockout of either the eIF5A-1 gene (Eif5a) or of the deoxyhypusine synthase gene (Dhps) caused early embryonic lethality in mice, indicating the essential nature of both eIF5A-1 and deoxyhypusine synthase in mammalian development.

Biological Relevance and Therapeutic Potential of the Hypusine Modification System

“…3A). This observation is well in line with data obtained in a mixed background published by others (43,44). Heterozygous Dhs ϩ/Ϫ animals were viable and did not show any obvious phenotype.…”

“…Mice-To study the biological relevance and functional requirement of the hypusine modification in embryonic development (43,44) and for viability, we used a recently described conditional knock-out strain for Dohh (33) and established a new conditional knock-out mouse model for Dhs (B6.Dhps tm2a(EUCOMM)Wtsi ). For the generation of the latter strain, embryonic stem cell clones were obtained from the International Knock-out Mouse Consortium (30).…”

Fertility and Polarized Cell Growth Depends on eIF5A for Translation of Polyproline-Rich Formins in Saccharomyces cerevisiae

“…The connection between eIF5A and cancer development is further supported by studies indicating that overexpression of eIF5A-2 is associated with metastasis in several cancer types (Caraglia et al 2013). The knockout of eIF5A in mice causes early embryonic lethality, indicating a role in mammalian development (Nishimura et al 2012). In C. elegans, mutation of eIF5A produces slow larval growth, structural abnormalities, and sterile adults (Hanazawa et al 2004).…”

Role of polyamines, their analogs and transglutaminases in biological and clinical perspectives

“…Several contributions in this issue deal with this topic. Nishimura et al (2011) demonstrate that eIF5A-1 and deoxyhypusine synthase genes are essential for mouse embryonic development. Hyvönen et al (2011b) show that only those C-methylated spermidines that act as substrate for hypusine synthesis substitute natural spermidine in supporting cell growth.…”