IMPC: Importance of PABPs in mammalian reproduction and physiology

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The proteins that make up our cells are encoded by genes that serve as a genetic blueprint. The information stored in genes is expressed, or decoded, to produce proteins by a multi-step process known as gene expression. One key step is when the genetic code is copied to a template (mRNA) which is used to make proteins (mRNA translation). Thus the regulation of mRNA translation and destruction of the template (stability) are keys steps to making sure that cells and organisms need to make proteins at the right time, place and in the correct amount. When mRNA translation and stability are not properly regulated this can lead to a wide variety of diseases including cancer, metabolic, neurological and reproductive disorders. Poly(A)-binding proteins are central regulator of multiple steps in the gene expression pathway, including mRNA translation and stability. Mammals contain four very similar genes for members of this family, two of which (PABP1 and PABP4) are produced in many cell types throughout the body and two of which are mainly (ePABP)/only (tPABP) expressed in reproductive tissues. Whilst the functions of proteins have been extensively studied in cells, their roles in within the body remains less clear meaning that whole organism studies are required. Gaining a complete picture is is a long term goal, but work by ourselves and others have already established that they have important roles in processes associated with human reproductive and metabolic disorders. Collectively, we have found that one family member (ePABP) is essential for the ability to make eggs, this is important as roughly 10-15% of couples worldwide suffer from infertility. We have found that a second member (PABP4) also affects female fertility, but in this case it is due to problems during the later stages of pregnancy leading to growth problems whilst in the womb (intrauterine growth restriction) and late fetal death (stillbirth). Poor intrauterine growth predisposes human babies to health problems in adulthood including cardiovascular disease, stroke and type II diabetes, and stillbirth affects 5 times more babies than Down's syndrome in the UK (1/200). We have also found that PABP4 is important in regulating fat and glucose levels, especially on high fat (junk food) diets, meaning it may form part of the important link between obesity and type II diabetes, which accounts for 90% of the 3.9 million people affected by diabetes in the UK. These results illustrate the importance of further studying this family. Numerous lines of evidence lead us to believe that ePABP and PABP4 are also important for other processes within the body, and we may have missed these effects so far, due to both proteins being present within the same cell at the same time, substituting for one another. Thus we aim to use genetic methods to overcome this limitation in order to identify what additional processes they are involved in, for instance male fertility and whether the effects (e.g. metabolic) we have observed thus far get worse. This is a necessary stepping stone to understanding the full spectrum of the contribution of this family to human disease and to exploring their potential as a therapeutic target.