Fetal estrogens are not involved in sex determination but critical for early ovarian differentiation

AROMATASE, encoded by the CYP19A1 gene, is the cytochrome enzyme responsible for the synthesis of estrogens in vertebrates. In most mammals a peak of expression of the CYP19A1 gene occurs in the fetal XX gonad when sexual differentiation starts up. To elucidate the role of this peak, we produced 3 lines of TALEN genetically edited CYP19A1 KO rabbits, that were void of any production of estradiol. All KO XX rabbits developed as females, with aberrantly small sized ovaries at adulthood, an almost empty reserve of primordial follicles and very few large antrum follicles. Ovulation never occurred. Our histological, immunohistological and transcriptomic analyses showed that the surge of estradiol in the XX fetal rabbit gonad is dispensable for its determination as an ovary, or for meiosis. However, it is mandatory for the high proliferation and differentiation of both somatic and germ cells, and consequently for the establishment of the ovarian reserve.