Endocrine Abstracts (2003) 6 OC25

Sexual dimorphism in anterior pituitary function in the annexin 1 knockout mouse

CD John1, JF Morris2, HC Christian2, RJ Flower3 & JC Buckingham1

1Dept. of Neuroendocrinology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road London W12 ONN, UK; 2Laboratory of Cellular Endocrinology, Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK; 3Department of Biochemical Pharmacology The William Harvey Research Institute, Charterhouse Square London EC1M 6BQ, UK.

Immunoneutralisation and antisense studies have shown that the acute regulatory actions of glucocorticoids (GCs) on the secretion of corticotrophin (ACTH) from the anterior pituitary gland are dependent upon the 37 kDa protein, annexin 1 (Anxa1 [1]), which is localised mainly to the S100-positive folliculo-stellate (FS) cells that lie in close apposition with the endocrine cells. The aim of this study was to examine pituitary function in male and female mice lacking the Anxa1 gene (Anxa1-/-). Utilising an established (i)in vitro(/i) pituitary system (2) we demonstrated that the inhibitory actions of dexamethasone (100nM) on the forskolin-evoked (100micromolar) release of ACTH were maintained in the male Anxa1-/-. However, in the presence of dexamethasone (100nM), female Anxa1-/- tissue demonstrated significantly elevated basal and forskolin stimulated (p<0.05) ACTH responses compared to wild-types. Electron microscopy studies showed that male (but not female) Anxa1-/- exhibited an altered pituitary morphology compared to wild type tissue, characterised by a large increase in the number of corticotrophs, which appear relatively inactive. Due to the sex differences observed with Anxa1-/- pituitary tissue, we subsequently compared the expression of interleukin-6 (IL-6) in Anxa1-/- vs. wild type pituitary tissue since (i) IL-6 is secreted by pituitary FS cells and plays an important role in the control of pituitary function and proliferation and (ii) IL-6 responses in the anterior pituitary are modulated by estrogen. Unlike their wild-type counterparts, Anxa1-/- pituitary tissue significantly (p<0.01) over expressed IL-6 in males and significantly (p<0.05) under expressed IL-6 in females. Here, we report that mice lacking the Anxa1 gene exhibit a complex gender-dependent phenotype with respect to anterior pituitary function.

We are grateful to the Wellcome Trust for financial support.

1.Buckingham JC, Flower RJ 1997 Mol Med Today 3:296-302

2.Taylor AD, Cowell AM, Flower RJ, Buckingham JC 1993 Neuroendocrinology 58:430-439

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