Abstract
Insulin-like growth factor II mRNA-binding protein (IMP) 2 is one of the three homologues (IMP1-3) that belong to a conserved family of mRNA-binding proteins. Its alternative splice product is aberrantly expressed in human hepatocellular carcinoma, and it is therefore identified as HCC. Previous works have indicated that IMP1/ZBP1 (zipcode binding protein) is critical in axon guidance and regeneration by regulating localization and translation of specific mRNAs. However, the role of IMP2 in the nervous system is largely unknown. We used the synapsin promoter-driven adeno-associated viral (AAV) 9 constructs for transgene expression both in vitro and in vivo. These viral vectors have proven to be effective to transduce the neuron-specific overexpression of IMP2 and HCC. Applying this viral vector in the injury-conditioned dorsal root ganglion (DRG) culture demonstrates that overexpression of IMP2 significantly inhibits axons regenerating from the neurons, whereas overexpression of HCC barely interrupts the process. Quantitative analysis of binding affinities of IMPs to β-actin mRNA reveals that it is closely associated with their roles in axon regeneration. Although IMPs share significant structural homology, the distinctive functions imply their different ability to localize specific mRNAs and to regulate the axonal translation.
Highlights
Insulin-like growth factor II mRNA-binding proteins (IMPs) including isoformsIMP1-3 consist of two conical RNA-recognition motifs and four K-homology (KH) RNA binding domains, which are key elements for RNA binding [1,2]
IMP1 is known as the zipcode binding protein (ZBP1) [1], whereas an alternative splice product of IMP2 is aberrantly expressed in human hepatocellular carcinoma and identified as HCC
IMP1 and IMP3 are abundant in the embryonic brain, spinal cord, and dorsal root ganglion (DRG), as well as in other organs, and drop to barely detectable levels towards the end of embryogenesis [4,5,6]
Summary
Insulin-like growth factor II mRNA-binding proteins (IMPs) including isoformsIMP1-3 consist of two conical RNA-recognition motifs and four K-homology (KH) RNA binding domains, which are key elements for RNA binding [1,2]. Insulin-like growth factor II mRNA-binding proteins (IMPs) including isoforms. ZBP1 (IMP1) binds to β-actin mRNA via the 30 UTR and localizes it in the distal cellular compartment, such as nerve axons, while repressing its translation [9,10]. Our previous study demonstrated that axon regeneration capacity was compromised in the adult DRG neurons and crushed sciatic nerve of heterozygous ZBP1 (IMP1) mice due to reduced axonal ß-actin mRNA localization and its local translation, suggesting a role of ZBP1/IMP1 in facilitating axon regrowth [6]. With structural similarity to its isoforms, the role of persistent expression of IMP2 in the adult neural tissue is, yet to be known. Several studies indicate IMP2 in the regulation of neural precursor cell differentiation of the neocortex and guidance of axon pathway-finding during development [8,11]. Overexpression of IMP2 has been associated with cancer cell proliferation and migration, and its role in poor prognosis of cancers has been suggested [16,17,18]
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