BrunoL1 regulates endoderm proliferation through translational enhancement of cyclin A2 mRNA.

Developmental control of proliferation relies on tight regulation of protein expression. Although this has been well studied in early embryogenesis, how the cell cycle is regulated during organogenesis is not well understood. Bruno-Like RNA binding proteins bind to consensus sequences in the 3'UTR of specific mRNAs and repress protein translation, but much of this functional information is derived from studies on mainly two members, Drosophila Bruno and vertebrate BrunoL2 (CUGBP1). There are however, six vertebrate and three Drosophila Bruno family members, but less is known about these other family members, and none have been shown to function in the endoderm. We recently identified BrunoL1 as a dorsal pancreas enriched gene, and in this paper we define BrunoL1 function in Xenopus endoderm development. We find that, in contrast to other Bruno-Like proteins, BrunoL1 acts to enhance rather than repress translation. We demonstrate that BrunoL1 regulates proliferation of endoderm cells through translational control of cyclin A2 mRNA. Specifically BrunoL1 enhanced translation of cyclin A2 through binding consensus Bruno Response Elements (BREs) in its 3'UTR. We compared the ability of other Bruno-Like proteins, both vertebrate and invertebrate, to stimulate translation via the cyclin A2 3'UTR and found that only Drosophila Bru-3 had similar activity. In addition, we also found that both BrunoL1 and Bru-3 enhanced translation of mRNAs containing the 3'UTRs of Drosophila oskar or cyclin A, which have been well characterized to mediate repression. Lastly, we show that it is the Linker region of BrunoL1 that is both necessary and sufficient for this activity. These results are the first example of BRE-dependent translational enhancement and are the first demonstration in vertebrates of Bruno-Like proteins regulating translation through BREs.