TFAP2C is a key regulator of intrauterine trophoblast cell invasion and deep hemochorial placentation

Abstract

The transcription factor AP-2 gamma (TFAP2C) has been identified as a key regulator of the trophoblast cell lineage and hemochorial placentation. The rat possesses deep placentation characterized by extensive intrauterine trophoblast cell invasion, which resembles human placentation. Initially, we examined Tfap2c expression in the rat placentation site and demonstrated its presence in multiple trophoblast cell lineages, including invasive trophoblast cells situated within the uterine-placental interface. Global genome-editing was used to explore the biology of Tfap2c in rat placentation. Homozygous global disruption of Tfap2c resulted in prenatal lethality between gestation days 8.5 and 9.5. Although, global disruption of one Tfap2c allele was compatible with survival, this heterozygous condition was surprisingly associated with diminished invasive trophoblast cell infiltration into the uterus. Since Tfap2c is expressed in multiple trophoblast cell lineages, we next explored the role of TFAP2C in the invasive trophoblast cell lineage using Cre-lox conditional mutagenesis. Invasive trophoblast cell-specific disruption of Tfap2c resulted in inhibition of intrauterine trophoblast cell invasion and intrauterine and postnatal growth restriction. In contrast to the global disruption of Tfap2c, the invasive trophoblast cell lineage was not impaired following conditional monoallelic disruption of Tfap2c. In summary, TFAP2C contributes to the progression of distinct stages of placental development. TFAP2C is a driver of early events in trophoblast cell development and reappears later in gestation as an essential regulator of the invasive trophoblast cell lineage. A subset of TFAP2C actions on trophoblast cells are dependent on gene dosage.