The role in neural patterning of translation initiation factor eIF4AII; induction of neural fold genes.

Expression of the RNA-helicase translation initiation factor, eIF4AII, in animal cap explants of Xenopus specifically upregulates genes expressed early in the neural plate border such as Xsna, Xslu, Pax-3 and XANF and also the cement gland marker XCG-1. eIF4AII is expressed specifically in the prospective neurectoderm from stage 11.5 and appears to have a significant role in mediating early patterning of the neurectoderm. It is induced by all known neural inducing regimes including secreted factors such as noggin, follistatin and chordin, transcription factors such as XlPou-2 and constructs that overcome repression of neural induction (tBMP-4R, lim-m3 and Xbra delta 304). It is also upregulated when neurulization occurs in embryonic ectoderm that has been disaggregated and reaggregated. While high amounts of injected mRNA of the neural inducers noggin, tBMP-4R and Xlpou-2 downregulate Xslu and upregulate the neural plate NCAM, smaller amounts of these mRNAs activate expression of eIF4AII and Xslu and suppress expression of epidermal keratin in animal cap assays. Ectopic expression of eIF4AII mRNA also upregulates transcription of the PKC alpha and beta genes. The sensitivity of the upregulation of neurectodermal markers to GF109203X indicates that the activity of a calcium activated protein kinase C (PKC) is also required. Furthermore ectopic expression of mouse eIF4AII mRNA upregulates the endogenous eIF4AII gene by a process that requires the activity of PKC. The effects of eIF4AII appear to be direct as conditional expression of eIF4AII in animal cap explants at the equivalent of stage 11.5 induces the endogenous eIF4AII and neural fold genes within 40 minutes. Expression of eIF4AII and activation of PKC sensitizes the embryonic ectoderm to the neuralising effect of noggin. We suggest that in developing embryos the neuralizing signal emanating from the organiser at first induces eIF4AII and the prospective neural crest in an arc low on the dorsal aspect of the embryo. As the neuralizing signal increases in intensity close to the organizer region, the tissue becomes committed to a neural plate phenotype. Expression of Xash-3A may suppress further expression of neural plate border genes within the prospective neural plate thereby subdividing the neurectoderm into two distinct regions.