Ftdc1/2, maternal-effect genes required for methylation maintenance and embryonic development

The oocyte serves the different purpose of transmitting the maternal genome and factors that are critical for post-fertilization events. Through the screening of oocyte-specific factors, here we identify two hitherto uncharacterized murine genes, ferritin domain containing 1 and 2 (Ftdc1 and Ftdc2), as novel maternal-effect genes. Genetic ablation of Ftdc1 or Ftdc2 causes postimplantation defects and female infertility, despite having little impact on oogenesis and preimplantation development. Nevertheless, post-transcriptional events in these mutant oocytes are disrupted. Importantly, FTDC1 or FTDC2 depletion induces the progressive loss of genomic methylation in early embryos. This loss correlates with a marked reduction in oocyte-specific DNA methyltransferase 1 (DNMT1o) protein, due to its increased degradation via the ubiquitin-proteasome pathway. Mechanistically, we reveal that FTDC1, FTDC2 and DNMT1o form a complex by direct interactions, thereby stabilizing each other. Moreover, comparison with DNA and histone methylation profiles in Dnmt1-null embryos indicates the functional uniqueness of FTDC1/2. These findings demonstrate that maternal FTDC1 and FTDC2 are crucial players in maintaining DNA methylation during embryogenesis and determining female fertility, offering new insights into the epigenetic control of mammalian development.