Reassessing the role of progesterone receptor isoforms PGR-A and PGR-B in female fertility

Progesterone is a critical reproductive hormone that acts via progesterone receptor transcriptional regulators. The short PGR-A isoform lacks a 164–amino acid amino-terminal region present in PGR-B that markedly enhances transcriptional activity. Isoform-specific mutants inactivating either PGR-A (PRAKO) or PGR-B (PRBKO) indicated that PGR-A is specifically essential for female fertility. This study revises that interpretation by showing that an inadvertent frameshift mutation in the PRAKO caused ablation of both isoforms, not the intended PGR-A isoform–specific mutation. A true PGR-A–specific mutant generated through CRISPR-Cas9 editing with a complete lack of PGR-A but retained PGR-B expression showed a phenotype indistinguishable from wild type. Thus, while the short PGR-A isoform has distinct function, it is not independently essential for female reproduction in mice, and the physiological role of these highly conserved isoforms must be reconsidered in light of this new information.