Annexin 1 gene deletion induces gender-specific changes in brain dopaminergic systems and prolactin secretion and their sensitivity to modulation by sex-steroids.

Patricia Cover1, Caroline McCulley1, Christopher John1, John Morris2, Helen Christian2, Julia Buckingham1. 1Imperial College London, London, United Kingdom, 2University of Oxford, Oxford, United Kingdom.

Our previous studies identified a role for annexin 1 (ANXA1), a Ca2+ and phospholipid binding protein, as an intra-pituitary modulator of prolactin secretion (1). To advance our understanding of the role of ANXA1 in this regard, we have examined the effects of ANXA1 gene deletion on the prolactin system and its sensitivity to manipulation of the sex steroid milieu in adult mice of both sexes. Electron microscopic analysis showed that lactotroph morphology and cell number were unaffected by ANXA1 gene deletion, irrespective of gender. However, serum prolactin was raised and pituitary prolactin content reduced in male ANXA1-null (KO) mice vs. wild-type (WT) controls (for plasma KO = 79.7+/-11.3 ng/ml vs. WT = 31.2+/-7.9 ng/ml, P<0.05. n = 12-14; for pituitary KO = 23.3+/-9.2 ng/ml vs. WT = 97.4+/-38.3 ng/ml, P<0.05, n = 12). No such changes were evident in female mice which showed higher serum and pituitary prolactin levels than their male counterparts irrespective of genotype (P<0.01). Gonadectomy increased serum prolactin in male WT mice (P<0.05) but testosterone (80μg/day s.c.) was without effect. By contrast, in male ANXA1-null mice serum prolactin was unaffected by gonadectomy but increased by testosterone treatment (P<0.05). In females serum prolactin was unaffected by gonadectomy irrespective of genotype but increased by oestradiol-17β (E2, 80ng ml s.c) treatment in WT (P<0.05) but not in ANXA1-null mice. Within the brain, ANXA1 gene deletion had no effect on the number of tyrosine hydroxylase positive (TH+) cells in the arcuate nucleus (AN), periventricular nucleus (PeN) or substantia nigra pars compacta (SNpc) of male or female mice, nor did it affect the sensitivity of the SNpc to a neurotoxic challenge (6-hydroxydopamine, 2 or 8μg injected 2 weeks previously into the striatum). In males gonadectomy increased TH+ cell number in the PeN but not the AN irrespective of genotype (P<0.05) while testosterone increased AN but not PeN TH+ cell number in WT but not ANXA1-null mice (P<0.05). In the female AN TH+ cell number was unaffected by gonadectomy or E2 treatment in mice of either strain, while PeN TH+ cell number was increased by gonadectomy in WT (P<0.05), but not in ANXA1-null mice, but unaffected by E2 treatment. In contrast to the prolactin system, there were no significant between strain differences in serum LH in mice of either sex before or after gonadectomy or treatment with testosterone or E2. The results support the premise that ANXA1 contributes to the mechanisms regulating prolactin secretion and indicate that its role is gender-specific. They also provide novel evidence that ANXA1 gene deletion induces locus-specific changes in the responsivity of the neuroendocrine system to sex steroids. If these changes extend to other tissues, they may underpin some of the surprising sexual dimorphisms the ANXA1-null mouse shows (2).

Taylor AD et al. (2000). Endocrinology 141:2209-19
Hannon R et al. (2003) FASEB J 17: 253-5.

Generously supported by the Wellcome Trust.