Galanin regulates prolactin release and lactotroph proliferation

Abstract

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 colocalize in the same secretory granule, the expression of both proteins is extremely sensitive to the estrogen status of the animal. The administration of estradiol-17␤ induces pituitary hyperplasia followed by adenoma formation and causes a 3,000-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 with wild-type controls. Mutant females fail to lactate and pups die of starvation͞dehydration unless fostered onto wild-type mothers. Prolactin secretion in mutant females is markedly reduced at 7 days postpartum compared with 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 estrogen, 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 coordinated increase in prolactin release and the number of lactotrophs, with a marked involution in their number once lactation ceases (1-4). 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 (5). However, in autopsy series of elderly females the prevalence is 1,000-fold greater, emphasizing that most prolactinomas are clinically silent and common in the elderly population (6). Prolactinomas are also a common cause of death in female aged rats of a number of strains (7-9). Treatment of prolactinomas with dopamine agonists reduces pituitary prolactin expression and reverses lactotroph hyperplasia, emphasizing the link between prolactin expression and cellular proliferation. Prolactinomas arise as monoclonal neoplasms, indicating that one or more somatic mutations underlie tumor pathogenesis. A large and increasing body of literature has failed to identify mutations in known protooncogenes in human prolactinomas (10-12). In contrast, exogenous estro...

A role for galanin in human and experimental inflammatory demyelination

“…Gal-OE mice (20), which fully recapitulate the endogenous expression pattern of galanin in the intact animal and inducibly overexpress the peptide following axotomy (21), were compared with lines carrying loss-of-function mutations in the galanin peptide (22) (Gal-KO) and GalR2 (23) (GalR2-MUT). Gal-OE (line OE2) mice (20) were completely resistant to the development of any clinical disease in the EAE model, compared to strain-, age-, and sex-matched WT controls, with cumulative total EAE scores (equivalent to the area under the curve (AUC) of the mean EAE clinical score against time) of 0.1 Ϯ 0.1 vs. 26.1 Ϯ 1.9, P Ͻ 0.001 (Fig.…”

“…Details of the strain and breeding history have been previously described (22). In brief, mice homozygous for a targeted mutation in the galanin gene were generated using the E14 cell line.…”

Distribution and regulation of galanin receptor 1 messenger RNA in the forebrain of wild type and galanin-transgenic mice

“…All efforts were made to minimize the number of animals used and to reduce their discomfort. The GALTG and GALKO mice were developed and characterized as previously described (Holmes et al, 2000;Mazarati et al, 2000;Steiner et al, 2001;Wynick et al, 1998).…”

“…One model was a transgenic mouse that overexpresses galanin under the control of the dopamine ␤-hydroxylase promoter (galanin transgenic [GALTG]) (Mazarati et al, 2000;Steiner et al, 2001). The other model was a mouse with a targeted deletion of the galanin gene (GALKO) (Wynick et al, 1998). We postulated that to maintain homeostasis in galanin signaling, the expression of GALR1 mRNA would be altered during development in compensation for the reduction or overabundance of the ligand in galanin-mutant mice.…”

Enhanced hippocampal noradrenaline and serotonin release in galanin-overexpressing mice after repeated forced swimming test

“…Recently, mice with a targeted disruption of the galanin gene (12), or overexpressing galanin under the dopamine ␤-hydroxylase (D␤H) promoter (GalOE͞D) (13, † †) or the plateletderived growth factor B promoter (GalOE͞P) (14, ‡ ‡), have been generated and characterized with regard to several functional parameters (see refs. 15 …”