Alpha-fetoprotein controls female fertility and prenatal development of the gonadotropin-releasing hormone pathway through an antiestrogenic action.
It has been shown previously that female mice homozygous for an alpha-fetoprotein (AFP) null allele are sterile as a result of anovulation, probably due to a defect in the hypothalamic-pituitary axis. Here we show that these female mice exhibit specific anomalies in the expression of numerous genes in the pituitary, including genes involved in the gonadotropin-releasing hormone pathway, which are underexpressed. In the hypothalamus, the gonadotropin-releasing hormone gene, Gnrh1, was also found to be down-regulated. However, pituitary gene expression could be normalized and fertility could be rescued by blocking prenatal estrogen synthesis using an aromatase inhibitor. These results show that AFP protects the developing female brain from the adverse effects of prenatal estrogen exposure and clarify a long-running debate on the role of this fetal protein in brain sexual differentiation.
Université Libre de Bruxelles, IBMM, Laboratoire de Biologie du Développement, Rue Pr. Jeener & Brachet 12, B-6041 Gosselies (Charleroi), Belgium. cdemees@ulb.ac.be.
Christelle
C
De Mees
Jean-François
JF
Laes
Julie
J
Bakker
Johan
J
Smitz
Benoît
B
Hennuy
Pascale
P
Van Vooren
Philippe
P
Gabant
Josiane
J
Szpirer
Claude
C
Szpirer
D000733:Androstatrienes / Q000494:pharmacology; D000818:Animals; D047072:Aromatase Inhibitors / Q000494:pharmacology; D001921:Brain / Q000196:embryology; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005298:Fertility / Q000235:genetics*; D047109:Fetal Development / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics; D007031:Hypothalamus / Q000502:physiology; D007247:Infertility, Female / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010902:Pituitary Gland / Q000502:physiology; D010906:Pituitary Hormone-Releasing Hormones / Q000378:metabolism*; D011247:Pregnancy; D011498:Protein Precursors / Q000235:genetics; D000509:alpha-Fetoproteins / Q000235:genetics / Q000378:metabolism*
C115984:1,4,6-androstatrien-3,17-dione; D000733:Androstatrienes; D047072:Aromatase Inhibitors; D004967:Estrogens; D010906:Pituitary Hormone-Releasing Hormones; D011498:Protein Precursors; D000509:alpha-Fetoproteins; C050866:progonadoliberin I; D007987:Gonadotropin-Releasing Hormone