Targeted Overexpression of Galanin in Lactotrophs of Transgenic Mice Induces Hyperprolactinemia and Pituitary Hyperplasia1

Abstract

We generated transgenic mice that carry 4.6 kb of the mouse galanin gene fused to 2.5 kb of the rat PRL promoter. In all transgenic lines that carried and transmitted the transgene, there were significant increases in galanin messenger RNA and peptide levels in the anterior pituitary in both male and female transgenic mice, and the elevation of galanin was restricted to the anterior lobe. Furthermore, galanin release from pituitary cells in vitro of both male and female transgenic mice was dramatically increased compared with that in control mice. At 2-4 months of age, pituitary PRL contents in female transgenic mice were increased compared with those in normal controls. Moreover, PRL messenger RNA levels were increased in female transgenic mice. However, plasma levels of PRL in female transgenic mice were not significantly higher until 6 months of age. By 11 months of age, cell numbers in the anterior pituitary were increased in female, but not male, transgenic mice. The percentage of lactotrophs in female transgenic mice as well as PRL gene expression per cell were significantly higher. No differences were detected in PRL content, gene expression, or release between normal and transgenic male mice. Six weeks of estrogen treatment significantly increased anterior pituitary weights and PRL secretion in male transgenic mice compared with that in normal male mice. In addition, anterior pituitary weights and PRL secretion were decreased in female transgenic mice compared with controls 6 weeks after ovariectomy. We conclude that overexpression of galanin in lactotrophs stimulates PRL synthesis and secretion and acts as a growth factor resulting in the formation of pituitary hyperplasia and hyperprolactinemia. Furthermore, estrogen appears critical for these galanin-mediated events.

Neurohypophyseal Neuregulin 1 Is Derived from the Hypothalamus as a Potential Prolactin Modulator

“…Moreover, evidence indicates that PRL regulation appears to be a multiple factor-promoted process. Although hypothalamus-derived dopamine and thyrotropin-releasing hormone are the main sources of PRL regulation in the AP, other substances also control PRL expression and secretion [23,24,25]. Clinically, patients with ectopic PP and interrupted PS have been reported to exhibit hyperprolactinemia during childhood [26,27].…”

The Neuropeptide Galanin Augments Lobuloalveolar Development

“…Galanin is also a mitogen for the prolactin-secreting pituitary lactotroph cells. Overexpression of galanin in the lactotroph induces hyperplasia and consequent hyperprolactinemia (16), and galanin knockout (Gal Ϫ/Ϫ ) mice display reduced prolactin levels during pregnancy associated with lactational failure (17). Together these data demonstrate an essential role for galanin in the control of neuronal and neuroendocrine function.…”

Co-aggregation and secondary nucleation in the life cycle of human prolactin/galanin functional amyloids

“…However, a substantial decrease in physiological PRL levels would inevitably affect the storage of GAL and its subsequent release as they are in a positive feedback loop. On the other hand, over-production of GAL may result in hypersecretion of PRL-leading to prolactinoma 99 . Therefore, tight regulation is required for GAL synthesis and secretion.…”