Nr5a1 suppression during the fetal period optimizes ovarian development by fine-tuning of Notch signaling

Abstract

The nuclear receptor NR5A1 is equally expressed and required for development of the gonadal primordia of both sexes, but after sex determination, it is up-regulated in XY testes and down-regulated in XX ovaries. We have recently demonstrated that this down-regulation is mediated by Forkhead box L2 (FOXL2) and hypothesized that adequate suppression of Nr5a1 may be essential for normal ovarian development. Further, analysis of human patients with Disorders/Differences of Sex Development suggests that overexpression of NR5A1 can result in XX (ovo)testicular development. Here, we tested the role of Nr5a1 by overexpression in fetal gonads using a Wt1-BAC (bacterial artificial chromosome) transgene system. Enforced Nr5a1 expression compromised ovarian development in 46,XX mice, resulting in late onset infertility, but did not induce (ovo)testis differentiation. The phenotype was similar to that of XX mice lacking Notch signaling. The expression level of Notch2 was significantly reduced in Nr5a1 transgenic mice, and the ovarian phenotype was almost completely rescued by in utero treatment with a NOTCH2 agonist. We conclude that suppression of Nr5a1 during the fetal period optimizes ovarian development by fine-tuning of Notch signaling.