Evidences of a role for eukaryotic translation initiation factor 5A (eIF5A) in mouse embryogenesis and cell differentiation

Abstract

Eukaryotic translation initiation factor 5A (eIF5A) has a unique character: the presence of an unusual amino acid, hypusine, which is formed by post-translational modifications. Even before the identification of hypusination in eIF5A, the correlation between hypusine formation and protein synthesis, shifting cell proliferation rates, had already been observed. Embryogenesis is a complex process in which cellular proliferation and differentiation are intense. In spite of the fact that many studies have described possible functions for eIF5A, its precise role is under investigation, and to date nothing has been reported about its participation in embryonic development. In this study we show that eIF5A is expressed at all mouse embryonic post-implantation stages with increase in eIF5A mRNA and protein expression levels between embryonic days E10.5 and E13.5. Immunohistochemistry revealed the ubiquitous presence of eIF5A in embryonic tissues and organs at E13.5 day. Interestingly, stronger immunoreactivity to eIF5A was observed in the stomodeum, liver, ectoderm, heart, and eye, and the central nervous system; regions which are known to undergo active differentiation at this stage, suggesting a role of eIF5A in differentiation events. Expression analyses of MyoD, a myogenic transcription factor, revealed a significantly higher expression from day E12.5 on, both at the mRNA and the protein levels suggesting a possible correlation to eIF5A. Accordingly, we next evidenced that inhibiting eIF5A hypusination in mouse myoblast C2C12 cells impairs their differentiation into myotubes and decreases MyoD transcript levels. Those results point to a new functional role for eIF5A, relating it to embryogenesis, development, and cell differentiation.

Genome-Wide Exploration of miRNA Function in Mammalian Muscle Cell Differentiation

“…CNOT6L is a subunit of the CCR4 complex [25], which controls gene expression at multiple levels, including shortening of mRNA polyA tails in the cytoplasm, and a repressor of p27, a proliferation inhibitor required for differentiation [26]. Exportin-4 (XPO4) is a nuclear export protein that inhibits EIF5A2 [27], a translation regulator that seems to be important for skeletal muscle cell differentiation [28].…”

Gene expression profiling of gastrocnemius of “minimuscle” mice

“…Gabarap is a known atrophy gene (24) and is upregulated in cisplatin-induced atrophy of C2C12 myotubes (9). Eukaryotic initiation factor 5a (Eif5a) undergoes a unique posttranslational modification (hypusination) that correlates with embryonic myogenic differentiation, and inhibition of EIF5A hypusination impairs C2C12 differentiation (33). Clec10a (MGL1) regulates inflammatory processes, and MGL1 Ϫ/Ϫ mice are protected from glucose intolerance and insulin resistance associated with diet-induced obesity due to diminished adipose tissue macrophage response (44).…”

Upregulation of eIF-5A1 in the paralyzed muscle after spinal cord transection associates with spontaneous hindlimb locomotor recovery in rats by upregulation of the ErbB, MAPK and neurotrophin signal pathways

“…Tissues at the stage of differentiation have a higher content of eIF-5A [22]. It has also been reported that eIF-5A stimulates the differentiation and proliferation of various cells, such as multipotent adult germline stem cells, embryonic stem cells and corneal epithelial cells [22,28,29]. However, the mechanism of eIF-5A involved in protein synthesis has been a subject of controversy for decades.…”

“…Up to date, there is no study to address the role of eIF-5A1 in muscle function following SCI. While evidence indicates that eIF-5A is involved in mouse embryogenesis and cell differentiation [22], one report shows that eIF-5A is also involved in stem cell differentiation in skeletal muscle [23], suggesting that eIF-5A could correlate with muscle development and muscle reflex arc plasticity.…”