A Dynamic Software Product Line Approach Using Aspect Models at Runtime

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 upregulated in XY testes and downregulated in XX ovaries. We have recently demonstrated, in mice, that this downregulation is mediated by forkhead box L2 (FOXL2) and hypothesized that adequate suppression of <i>Nr5a1</i> is essential for normal ovarian development. Further, analysis of human patients with disorders/differences of sex development suggests that overexpression of <i>NR5A1</i> can result in XX (ovo)testicular development. Here, we tested the role of <i>Nr5a1</i> by overexpression in fetal gonads using a <i>Wt1</i>-BAC (bacterial artificial chromosome) transgene system. Enforced <i>Nr5a1</i> 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 <i>Notch2</i> was significantly reduced in <i>Nr5a1</i> transgenic mice, and the ovarian phenotype was almost completely rescued by <i>in utero</i> treatment with a NOTCH2 agonist. We conclude that suppression of <i>Nr5a1</i> during the fetal period optimizes ovarian development by fine-tuning Notch signaling.