Developmental Regulation by Tis11

Drosophila Chromosome Structure Group

The levels of mRNA in cells reflect a balance between rates of gene transcription and rates of mRNA turnover. Although attention has focused on the control of transcription in the regulation of gene expression, the rates of mRNA turnover can be just as important in determining final mRNA concentrations. Rather than a single default pathway of mRNA decay, rates of mRNA turnover can differ dramatically among different mRNA species in a given cell type, between the same mRNA species in different cells and with the same mRNA species and cell type when cells are exposed to distinct environmental stimuli.

It is clear that the turnover rate of some mRNAs can be influenced by cis-acting sequences, often within the 3' UTR. One of the best-studied examples is the AU-rich element (ARE). Several years ago, the Polypeptide Hormone Action Group, headed by Perry Blackshear, M.D., D. Phil., at the NIEHS Laboratory of Neurobiology, identified one ARE binding protein that can bind to AREs in the mRNAs encoding TNF and GM-CSF and lead to their destabilization, through a process that may involve the removal of the poly(A) tail, or deadenylation. There are three other mammalian members of this protein family with very similar CCCH zinc finger motifs. All of these proteins can act to promote the deadenylation and instability of mRNA targets that contain AREs.

To fully understand the molecular nature of how these proteins act to promote mRNA deadenylation and destruction, the group has chosen to use Drosophila melanogaster as a model system, because it is a genetically tractable organism that expresses only a single member of this protein family (TIS11). The Tis11 gene, however, may be differentially spliced to produce two different proteins. Essentially nothing is known about the function of this protein in Drosophila, although its transcript is expressed throughout development. In collaboration with Blackshear’s group, the Drosophila Chromosome Structure Group has obtained insertion mutants that develop slowly and fail to enclose, although in some genetic backgrounds a few escapers with impaired appendages survive.

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