The Neuropeptide Galanin Augments Lobuloalveolar Development

Abstract

Mammary lobuloalveolar development during pregnancy is controlled by ovarian sex steroids and pituitary prolactin release. In organ culture these hormones are incapable of reproducing the density and size of lobuloalveoli seen in mice, suggesting the existence of other undiscovered factors. We showed previously that galanin knockout mice fail to lactate sufficiently for pup survival following their first pregnancy. Here we demonstrate that prolactin treatment of galanin knockout mice allows pup survival but does not completely rescue lobuloalveolar development or reduced milk protein expression. When galanin was used in combination with prolactin in mammary organ culture, larger and more numerous lobules were produced than with prolactin alone. Galanin alone produced sustained activation of STAT5a and the induction of milk protein expression but did not induce lobulogenesis. Examination of the transcriptional interaction between galanin and prolactin using oligonucleotide microarrays demonstrated synergistic and antagonistic modes of interaction between these hormones. These data establish a new role for galanin as a hormone augmenting mammary development during pregnancy in concert with prolactin.Development of the mammary gland occurs predominantly after birth and is systemically controlled by the pituitaryovarian axis. A small number of hormones control the different facets of mammary development; for example, estrogen and growth hormone regulate ductal elongation, and progesterone is essential for ductal side branching and alveolar bud formation (1-3). Prolactin (PRL), 1 via support of ovarian steroid hormone synthesis and direct action on the mammary epithelial cells, is critical for two stages of mammary development, lobuloalveolar development during early pregnancy and lactogenesis during late pregnancy (4, 5). Other factors may remain to be discovered, as models of mammary development in vitro do not reproduce the extent of mammary development seen in vivo.Galanin is a 29-amino acid peptide originally isolated from porcine intestine (6) that has been implicated in the control of a number of biological processes including cognition, feeding behavior, neuroendocrine responses, mitogenesis, and nociception (7). Galanin signals through a family of three G proteincoupled receptors, galanin receptors (Galr) 1-3 (8 -10). The generation of mice carrying a loss-of-function mutation of the galanin gene has enabled investigation of the functions of galanin in vivo. Galanin regulates the development of sensory and cholinergic neurons, hippocampal excitability, and modulation of the pain response (11-14). Overexpression of galanin in neurons suppresses epileptic-like-induced seizures (15). 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 dat...

Elf5 is essential for early embryogenesis and mammary gland development during pregnancy and lactation

“…Since disruptions in either Elf5 or Prlr produce a similar phenotype, it is likely that Elf5 and Prlr participate in the same pathway. This study and the one by Naylor et al (2003) support that a possible downstream link for Elf5 is in the prolactin signalling pathway.…”

“…In order to determine if the defect in mammary gland development observed in Elf5 heterozygous females was due to the lack of Elf5 in the mammary epithelium per se or whether the defect was secondary due to defects in other endocrine systems, we transplanted wild‐type and Elf5 +/− mammary epithelium (Naylor et al , 2003) into Rag1 −/− recipient females (Mombaerts et al , 1992), which cannot reject transplants due to their compromised immune systems. These females were then mated.…”

Thyroid hormone responsive protein Spot14 enhances catalysis of fatty acid synthase in lactating mammary epithelium

“…In contrast to other mouse models with severe lactation failure, such as the DGAT 1-null, prolactin receptor +/ Ϫ , STAT5a-null, ELF5 +/ Ϫ , ␣ -lactalbumin-null, and galanin-null mice (58)(59)(60)(61)(62)(63), the lactation phenotype in Spot14-null dams is mild and no lactation defect was observed for MMTVSpot14 overexpressing dams ( Fig. 1A, B ).…”

Expression of NGF, BDNF and their high-affinity receptors in ovine mammary glands during development and lactation

“…It should be underpinned that, in ruminant, large mammary development occurs during pregnancy (Capuco and Ellis 2005). Indeed, the neuregulin/heregulin-1 (Nrg), an ErbB4 ligand, was demonstrated to play a role in lobuloalveolar development at pregnancy (Yang et al 1995) and also the neuronal peptide galanin (Gal) has been shown to directly modulate the formation of alveolar structures during pregnancy (Naylor et al 2003).…”