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. 2008 Jun;68(7):981-95.
doi: 10.1002/dneu.20638.

Sex differences in brain developing in the presence or absence of gonads

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Sex differences in brain developing in the presence or absence of gonads

Tomaz Büdefeld et al. Dev Neurobiol. 2008 Jun.

Abstract

Brain sexual differentiation results from the interaction of genetic and hormonal influences. This study used a unique agonadal mouse model to determine relative contributions of genetic and gonadal hormone influences in the differentiation of selected brain regions. SF-1 knockout (SF-1 KO) mice are born without gonads and adrenal glands and are not exposed to endogenous sex steroids during fetal/neonatal development. Consequently, male and female SF-1 KO mice are born with female external genitalia and if left on their own, die shortly after birth due to adrenal insufficiency. In this study, SF-1 KO mice were rescued by neonatal adrenal transplantation to examine their brain morphology in adult life. To determine potential brain loci that might mediate functional sex differences, we examined the area and distribution of immunoreactive calbindin and neuronal nitric oxide synthase in the preoptic area (POA) and ventromedial nucleus of the hypothalamus, two areas previously reported to be sexually dimorphic in the mammalian brain. A sex difference in the positioning of cells containing immunoreactive calbindin in a group within the POA was clearly gonad dependent based on the elimination of the sex difference in SF-1 KO mice. Several other differences in the area of ventromedial hypothalamus and in POA were maintained in male and female SF-1 KO mice, suggesting gonad-independent genetic influences on sexually dimorphic brain development.

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Figures

Fig. 1
Fig. 1
Digital images show calbindin immunopositive cells formed a distinct nucleus in caudal POA/AH in the brains from WT males only (a, arrow) while this nucleus was absent in all three other groups of mice (b- WT female, c – SF-1 knockout male, d – SF-1 knockout female; 3V – third ventricle, OT – optic tract).
Fig. 2
Fig. 2
Quantification of nNOS immunoreactivity in the caudal POA/AH analyzed as total immunoreactive area in coronal sections (mean ± S.E.M.) revealed statistically significant effect of sex in both WT and SF-1 knockout mice (p < 0.01) suggesting a gonadal hormone independent sex difference.
Fig. 3
Fig. 3
Digital images in the region of AVPV show both cell bodies and fibers were immunopositive for nNOS (a – WT male, b – WT female, c – SF-1 knockout male, d – SF-1 knockout female; 3V – third ventricle, OT – optic tract).
Fig. 4
Fig. 4
Quantification of nNOS immunopositive cells in the rostral AVPV area analyzed by rows (mean ± S.E.M.) revealed statistical significant interaction between location and sex (p < 0.05) with males of both genotypes having more cells than females throughout the region.
Fig. 5
Fig. 5
Digital images show calbindin immunopositive cells in the BSTM area in WT (a – male, b – female) and SF-1 knockout (c – male, d – female) mice. Bold black lines mark the BSTMPM area that was analyzed for cell numbers.
Fig. 6
Fig. 6
Quantification of calbindin immunopositive cells in the BSTMPM area analyzed as a total number of cells in the nucleus (mean ± S.E.M.) revealed statistical significant interaction of sex and genotype between WT and SF-1 knockout mice of both sexes (p < 0.05).
Fig. 7
Fig. 7
Digital images show nNOS immunopositive cells in BSTM area in WT (a – male, b – female) and SF-1 knockout (c – male, d – female) mice.
Fig. 8
Fig. 8
Digital images of the region of the VMH show calbindin immunopositive cells were concentrated in ventrolateral positions in WT males (a) and females (b), but were translocated to more dorsomedial positions in male (c) and female (d) SF-1 knockout mice. The third ventricle provides the left margin of the tissue in each image; ARC – arcuate nucleus, VMH – ventromedial nucleus.
Fig. 9
Fig. 9
Digital images of the region of the VMH show nNOS immunopositive cells were concentrated in ventrolateral positions in WT males (a) and females (b), but were translocated to more dorsomedial positions in male (c) and female (d) SF-1 knockout mice. The third ventricle provides the left margin of the tissue in each image; ARC – arcuate nucleus, VMH – ventromedial nucleus.
Fig. 10
Fig. 10
Quantification of calbindin immunopositive cells in the VMH area analyzed by columns relative to the 3rd ventricle (mean ± S.E.M.) revealed significant differences in the location of immunoreactive cells between WT and SF-1 knockout mice (p < 0.001).
Fig. 11
Fig. 11
Quantification of nNOS immunopositive cells in the VMH area analyzed by columns relative from 3rd ventricle (mean ± S.E.M.) also revealed significant interaction between sex, genotype and location (p < 0.01).

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