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Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens

Abstract

Two clearly opposing views exist on the function of alpha-fetoprotein (AFP), a fetal plasma protein that binds estrogens with high affinity, in the sexual differentiation of the rodent brain. AFP has been proposed to either prevent the entry of estrogens or to actively transport estrogens into the developing female brain. The availability of Afp mutant mice (Afp−/−) now finally allows us to resolve this longstanding controversy concerning the role of AFP in brain sexual differentiation, and thus to determine whether prenatal estrogens contribute to the development of the female brain. Here we show that the brain and behavior of female Afp−/− mice were masculinized and defeminized. However, when estrogen production was blocked by embryonic treatment with the aromatase inhibitor 1,4,6-androstatriene-3,17-dione, the feminine phenotype of these mice was rescued. These results clearly demonstrate that prenatal estrogens masculinize and defeminize the brain and that AFP protects the female brain from these effects of estrogens.

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Figure 1: Complete absence of female sexual behavior in female mice lacking AFP.
Figure 2: Increased male-typical sexual behavior in female mice lacking AFP.
Figure 3: Neurochemical changes in female mice lacking AFP.
Figure 4: Prenatal treatment with the aromatase inhibitor ATD rescued the female phenotype of Afp2−/− females.

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Acknowledgements

This work was supported by grants from the National Institute for Child Health and Human Development (HD044897) and from the Fonds National de la Recherche Scientifique (1.5.082.04) to J. Bakker; a grant from the National Institute of Mental Health (MH50388) to J. Balthazart; and grants from the Fund for Collective Fundamental Research (2.4529.02 and 2.4565.04) and the Government of the “Communauté Française de Belgique” (“Action de Recherche Concertée” 00/05-250) to C. Szpirer. C. De Mees was supported by a fellowship from the Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture. J. Bakker is a Research Associate and C. Szpirer is a Research Director at the Fonds National de la Recherche Scientifique.

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Correspondence to Julie Bakker.

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Bakker, J., De Mees, C., Douhard, Q. et al. Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens. Nat Neurosci 9, 220–226 (2006). https://doi.org/10.1038/nn1624

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