Mammalian PABPC4 is non-essential, but has roles in growth, post-natal survival and haematopoiesis.

Abstract

Cytoplasmic poly(A)-binding proteins (PABPCs) are multifunctional RNA-binding proteins which play crucial roles in mRNA translation and stability. In mammals, two family members, PABPC1 and PABPC4 appear widely expressed, but the consequences of their loss of function in vivo remain unknown, despite PABPC4 being implicated in a variety of human diseases. We address this knowledge gap using a series of Pabpc4 knock-out mice. Unexpectedly, we reveal that mammalian PABPC4 is not essential for development, contrary to findings in non-mammalian vertebrates. However, its loss affects birth weight, post-natal growth trajectories and survival, although these were not tightly associated. Growth to adulthood was impacted in a sexually dimorphic manner. Viable Pabpc4-deficient mice allowed us to interrogate roles of Pabpc4 that may affect human health. Anaemia represents a large global health burden, and work in a red blood cell (RBC) model suggested a potential role in haemoglobin synthesis. Surprisingly in vivo, we find that Pabpc4 loss did not reduce haemoglobin levels but caused microcytic RBCs and altered RBC distribution width. Moreover, conditional genetic approaches established that this was not a red blood cell intrinsic effect. Taken together, this work provides unprecedented insights into the in vivo functions of mammalian PABPC4, and caution against inferring mammalian PABPC function from work in cell-based models and/or non-mammalian species. The generated mouse lines also form a valuable resource with which to further investigate the roles of PABPC4 in health and disease. Significance StatementRNA-binding protein (RBP)-mediated post-transcriptional regulation is essential for life and life-long health. Cytoplasmic poly(A)-binding proteins are family of RBPs that regulate multiple aspects of cytoplasmic mRNA fate. PABPC4 is an understudied family member, genetically associated with a wide range of human diseases. By creating a series of Pabpc4 knock-out mice, we surprisingly find it is not essential but is required for normal post-natal survival and growth and normal red blood cell development. Our results emphasise the importance of whole organism studies for understanding mammalian PABP function, uncovering differences between function inferred from other vertebrate species and prior cell-based work. The generated mice also provide a valuable resource for exploring its potential broad roles in human disease.