Padi6-KO Mouse

Padi6, or peptidyl arginine deiminase 6, is a maternal factor crucial for early embryonic development and a member of the subcortical maternal complex (SCMC) [2,3,4,5,6,8]. It is less conserved than other peptidyl arginine deiminases (PADIs) and currently has no reported catalytic activity [2]. While its exact molecular mechanisms remain unknown, it is suggested to be involved in processes like embryonic genome activation, cytoplasmic lattice formation, maternal mRNA and ribosome regulation, and organelle distribution [2].

In a mouse line with a Padi6 missense variant identified in a family with Beckwith-Wiedemann syndrome and multilocus imprinting disturbances (MLID), homozygous female mice showed embryo development interruption at the two-cell stage. Analyses revealed defective oocyte maturation, incomplete DNA demethylation, abnormal regulation of zygotic genome activation (ZGA) and maternal decay genes, and abnormal localization of DNMT1 and UHRF1 in oocytes and zygotes [1]. In female mice or women, deletion and mutations of Padi6 lead to early embryonic developmental arrest, female infertility, maternal imprinting defects, and trophoblast hyperproliferation [2]. In human trophoblast cells, Padi6 was found to regulate cell migration-invasion through the Hippo/YAP1 pathway, and mutations in Padi6 in humans can cause multiple reproductive deficiencies including hydatidiform moles and miscarriages [3]. Also, biallelic mutations in Padi6 in humans cause female infertility with early embryonic arrest [4,8,9,10]. Knocking out Padi6 in mice prevents the accumulation of essential proteins for early embryonic development on cytoplasmic lattices, resulting in early embryonic arrest [7].

In summary, Padi6 plays essential roles in oocyte maturation, pre-implantation epigenetic reprogramming, ZGA, and early embryonic development. Studies using gene knockout mouse models have been crucial in revealing its functions, especially in understanding its contribution to female infertility and early embryonic arrest, highlighting its significance in reproductive biology [1,2,3,4,7,8,9,10].