Premature ovarian insufficiency (POI) is characterised by loss of ovarian function before the age of 40. Mutations in EIF4ENIF1, an RNA-binding protein expressed in developing oocytes, have been linked with POI, and previous work has shown that Eif4enif1 knockdown promotes meiotic arrest in mouse oocytes. However, the mechanism by which EIF4ENIF1 might affect fertility is unclear. Here, Lin Li, Kehkooi Kee and colleagues generate Eif4enif1 heterozygous knockout mice to model the haploinsufficiency observed in human patients. They find that these mice produce smaller litters than wild-type mice. Young Eif4enif1-deficient mice are indistinguishable from wild-type mice in terms of ovary size and follicle number but, from 9 months of age, they exhibit a reduced number of follicles. Eif4enif1-deficient oocytes also exhibit maturation defects and dysregulated gene expression at both transcriptional and translational levels, including genes encoded by mitochondrial DNA. Transmission electron microscopy analyses suggest that mitochondrial dynamics in the Eif4enif1-deficient oocytes are disrupted. The distribution of the mitochondria-associated ribonucleoprotein domain (MARDO), a structure implicated in mRNA storage, is also aberrant in these oocytes. Overall, this work sheds new light on the molecular basis of the role of EIF4ENIF1 in oocyte development and may provide new targets for clinical studies.
