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IN PRODUCTION

Oocyte-restricted expression distinguishes Bmp15, the mouse ortholog of human BMP15, whose product is a TGF-beta superfamily ligand secreted by growing oocytes, largely as a covalent heterodimer with GDF9 known as cumulin. That heterodimer signals to adjacent granulosa cells through BMPR1B and BMPR2 with SMAD1, SMAD5, and SMAD8 phosphorylation, coordinating cumulus expansion, glycolytic support of the oocyte, and suppression of premature luteinization. Human heterozygous variants cause primary ovarian insufficiency, and ovine FecX alleles produce dose-dependent hyperprolificacy then sterility, illustrating a steep genotype to ovulation-rate relationship. Mouse nulls are viable with only modest subfertility, so a simple knockout is a weak model; instead, patient-specific missense knockins that impair proprotein processing or heterodimer formation better recapitulate human disease logic. Because Gdf9 partners with and partially covers this ligand, compound or allelic-series designs are advisable. Humanized knockins are the right platform for recombinant cumulin or in vitro maturation reagent testing against defined ovulation endpoints.

Tissue restricted knockout of Bmp15 keeps wild type function everywhere else. Breeding is often more robust, and the setup mirrors patient biology where mutations arise in a subset of cells.