Galanin regulates Prolaction release and lactotroph proliferation
Summary:
The neuropeptide galanin is predominantly expressed by the lactotrophs (the prolactin secreting cell type) in the rodent anterior pituitary and in the median eminence and paraventricular nucleus of the hypothalamus. Prolactin and galanin co-localise in the same secretory granule, the expression of both proteins is extremely sensitive to the oestrogen status of the animal. The administration of 17b oestradiol induces pituitary hyperplasia followed by adenoma formation and causes a three thousand fold increase in the galanin mRNA content of the lactotroph.
To further study the role of galanin in prolactin release and lactotroph growth we now report the generation of mice carrying a loss-of-function mutation of the endogenous galanin gene. There is no evidence of embryonic lethality and the mutant mice grow normally. The specific endocrine abnormalities identified to date, relate to the expression of prolactin. Pituitary prolactin message levels and protein content of adult female mutant mice are reduced by 30-40% compared to wild-type controls. Mutant females fail to lactate and pups die of starvation/dehydration unless fostered onto wild-type mothers. Prolactin secretion in mutant females is markedly reduced at 7 days post-partum compared to wild-type controls with an associated failure in mammary gland maturation. There is an almost complete abrogation of the proliferative response of the lactotroph to high doses of oestrogen, with a failure to up-regulate prolactin release, STAT5 expression or to increase pituitary cell number. These data further support the hypothesis that galanin acts as a paracrine regulator of prolactin expression and as a growth factor to the lactotroph.
The factors that regulate proliferation of the lactotroph are largely unknown. Further, the relationship of altered prolactin secretion to lactotroph proliferation is also unclear. Pregnancy induces a co-ordinated increase in prolactin release and the number of lactotrophs, with a marked involution in their number once lactation ceases. In contrast, a sustained and uncontrolled proliferation of lactotrophs culminates in the development of prolactin secreting adenomas (prolactinomas) resulting in inappropriate lactation. The prevalence of prolactinomas is an estimated 100 per million. However, in autopsy series of elderly females the prevalence is one thousand fold greater, emphasising that most prolactinomas are clinically silent and common in the elderly population. Prolactinomas are also a common cause of death in female aged rats of a number of strains. Treatment of prolactinomas with dopamine agonists reduces pituitary prolactin expression and reverses lactotroph hyperplasia, emphasising the link between prolactin expression and cellular proliferation. Prolactinomas arise as monoclonal neoplasms, indicating that one or more somatic mutations underlie tumour pathogenesis. A large and increasing body of literature has failed to identify mutations in known proto-oncogenes in human prolactinomas. In contrast, exogenous oestrogen administration to man or rodents, potently induces prolactin gene transcription and secretion and stimulates lactotroph proliferation and adenoma formation. The mechanism by which oestrogen-induced proliferation occurs is also unknown, but addition of 17 b-oestradiol to anterior pituitary cultures stimulates the production of a number of growth factors, the most marked increase being in the peptide galanin.
Galanin is principally synthesised, stored and released by a sub-population of lactotrophs in the rodent pituitary and is extremely sensitive to the oestrogen status of the animal. A marked elevation in the expression of pituitary galanin occurs during pregnancy, whereas galanin is down-regulated in hypothalamic magnocellular neurons during lactation. Exogenous17 b-oestradiol causes a six fold induction in the number of galanin secreting lactotrophs and a three thousand fold increase in anterior pituitary galanin mRNA content, whilst the peptide levels rise 500 fold. In contrast, ovariectomy almost abolishes pituitary galanin content. Our previous studies have demonstrated that galanin is a mitogen to the 235-1 clonal lactotroph cell line acting via a novel pituitary-specific galanin receptor. We have also shown that immunoneutralisation of locally secreted galanin profoundly inhibits prolactin release, particularly in the hyperoestrogenised state. A number of studies in man have confirmed our findings in rodents; human galanin infusion significantly stimulates prolactin secretion in normal female volunteers with an exaggerated response in patients with pituitary tumours.
Here we report the generation of mice carrying a loss-of-function mutation of the endogenous galanin gene. Prolactin expression is reduced in adult female mice and there is a failure to lactate following pregnancy. There is an almost complete abrogation of the proliferative response of the lactotroph to high doses of oestrogen, with a failure to up-regulate prolactin expression or to increase pituitary cell number. Galanin would therefore appear to act as tonic regulator of prolactin release and as a growth factor to the lactotroph.
D. Wynick, C.J. Small, A. Bacon, F.E. Holmes, M. Norman, C.J. Ormandy, E. Kilic, N.C.
Kerr, M. Ghatei, F. Talamantes, S.R. Bloom and V. Pachnis
Galanin regulates Prolaction release and lactotroph proliferation
PNAS, Vol.95, pp 12671 - 12676
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Dr. David Wynick
Department of Medicine
Bristol University
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