BAX-dependent and BAX-independent regulation of Kiss1 neuron development in mice - PubMed (original) (raw)

BAX-dependent and BAX-independent regulation of Kiss1 neuron development in mice

Sheila J Semaan et al. Endocrinology. 2010 Dec.

Abstract

The Kiss1 gene and its product kisspeptin are important regulators of reproduction. In rodents, Kiss1 is expressed in the hypothalamic arcuate (ARC) and anteroventral periventricular (AVPV)/rostral periventricular (PeN) nuclei. In the AVPV/PeN, females have more Kiss1 and tyrosine hydroxylase (TH) neurons than males. We explored the ontogeny of the Kiss1 sex difference, and the role of cell death in establishing Kiss1 and TH cell number. We also determined whether Kiss1 cells in AVPV/PeN coexpress TH. AVPV/PeN Kiss1 neurons were first detected in both sexes on postnatal d 10, but the Kiss1 sex difference did not emerge until postnatal d 12. The role of BAX-mediated apoptosis in generating this sex difference was tested in adult Bax knockout (KO) and wild-type mice. Deletion of Bax did not diminish the sex difference in Kiss1 expression in the AVPV/PeN. TH expression was sexually dimorphic in the AVPV of both wild-type and Bax KO mice but, unlike Kiss1, was not sexually dimorphic in the PeN of either genotype. Double-label analysis determined that most Kiss1 neurons coexpress TH mRNA, but many TH neurons do not coexpress Kiss1, especially in the PeN. These findings suggest that several subpopulations of TH cells reside within the AVPV/PeN, only one of which coexpresses Kiss1. In the ARC, Kiss1 cell number was markedly increased in Bax KO mice of both sexes, indicating that although BAX-dependent apoptosis does not generate the sex difference in either Kiss1 or TH expression in AVPV/PeN, BAX does importantly regulate Kiss1 cell number in the ARC.

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Figures

Figure 1

Figure 1

Development of the Kiss1 sex difference in the AVPV/PeN of mice. A, Representative photomicrographs of ISH for Kiss1 mRNA in the AVPV/PeN of male (M) and female (F) mice on PND 6, 10, and 14. B, Mean number of Kiss1 neurons in the AVPV/PeN of females and males over the course of early postnatal development. Kiss1 cells were first detected in each sex on PND 10. The number of Kiss1 neurons was significantly higher in females than males on PND 12 and later. C, Mean level of Kiss1 mRNA/cell in the AVPV/PeN of females and males over the course of early postnatal development. This measure was not significantly higher in females than males until PND 16. *, Significantly different from males of same age.

Figure 2

Figure 2

Representative photomicrographs of Kiss1 labeling in the AVPV and PeN of adult female (F) and male (M) WT and Bax KO animals. All animals were GDX and treated with E2 for 10 d before brain collection. 3V, Third ventricle.

Figure 3

Figure 3

Mean number of Kiss1 cells in the AVPV and PeN of adult WT and Bax KO females (F) and males (M) that were GDX and treated with E2 before killing. Kiss1 gene expression in both the AVPV (A) and PeN (B) was significantly higher in females than males in both genotypes. There were significantly more Kiss1 cells in Bax KO animals in the AVPV but not in the PeN. *, Significantly different from males of same genotype (P < 0.05).

Figure 4

Figure 4

Representative photomicrographs of TH expression in the AVPV and PeN of adult female (F) and male (M) WT and Bax KO animals. 3V, Third ventricle.

Figure 5

Figure 5

Mean number of TH cells in the AVPV (A) and PeN (B) of adult WT and Bax KO females (F) and males (M). TH cell number in the AVPV was significantly greater in females than males in both genotypes. In contrast, there was no significant sex difference in the PeN. *, Significantly different from males of same genotype (P < 0.05).

Figure 6

Figure 6

A, Representative photomicrographs of Kiss1-TH coexpression in the AVPV and PeN of adult female mice. Red DIG staining, Kiss1 mRNA; white silver grains, TH mRNA. Yellow arrows denote example double-labeled cells; light blue arrows denote single-labeled TH cells. B, Mean percentage of Kiss1 neurons coexpressing TH mRNA in the AVPV and PeN of adult male and female mice. C, Mean percentage of TH cells coexpressing Kiss1 mRNA in the AVPV and PeN of adult males and females. *, Significantly different from AVPV in same sex.

Figure 7

Figure 7

Representative photomicrographs of Kiss1 gene expression in the ARC of GDX adult WT and Bax KO mice. 3V, Third ventricle; cARC, caudal ARC; mARC, medial ARC.

Figure 8

Figure 8

A, Mean number of Kiss1 cells in the ARC of female (F) and male (M) Bax KO and WT animals that were GDX for 9 d before sacrifice. Kiss1 gene expression in the ARC was significantly higher in Bax KO mice than WT mice (P < 0.01), and this was especially true in males. *, Significantly different from female mice of same genotype.

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