Expression of Prolactin mRNA in Rat Mammary Gland During Pregnancy and Lactation

Iwasaka, Toshiki; Umemura, Shinobu; Kakimoto, Kochi; Koizumi, Haruko; Osamura, Yoshiyuki

doi:10.1177/002215540004800308

Cited by 25 publications

(15 citation statements)

References 29 publications

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“…Autocrine prolactin mRNA expression in the mammary gland has been detected in late-pregnant and lactating rats (Kurtz et al 1993;Steinmetz et al 1993;Iwasaka et al 2000;Ben-Jonathan et al 2008). In this regard, the sole report of a function for autocrine prolactin in a normal tissue arises from studies comparing proliferation rates in recombined mouse mammary glands composed of either Prl À/À or Prl +/+ epithelium transplanted into wild-type mammary stroma.…”

Section: Discussionmentioning

confidence: 99%

Autocrine prolactin induced by the Pten–Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways

et al. 2012

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Extrapituitary prolactin (Prl) is produced in humans and rodents; however, little is known about its in vivo regulation or physiological function. We now report that autocrine prolactin is required for terminal mammary epithelial differentiation during pregnancy and that its production is regulated by the Pten-PI3K-Akt pathway. Conditional activation of the PI3K-Akt pathway in the mammary glands of virgin mice by either Akt1 expression or Pten deletion rapidly induced terminal mammary epithelial differentiation accompanied by the synthesis of milk despite the absence of lobuloalveolar development. Surprisingly, we found that mammary differentiation was due to the PI3K-Akt-dependent synthesis and secretion of autocrine prolactin and downstream activation of the prolactin receptor (Prlr)-Jak-Stat5 pathway. Consistent with this, Akt-induced mammary differentiation was abrogated in Prl -/-mice. Furthermore, cells treated with conditioned medium from mammary glands in which Akt had been activated underwent rapid Stat5 phosphorylation in a manner that was blocked by inhibition of Jak2, treatment with an anti-Prl antibody, or deletion of the prolactin gene. Demonstrating a physiological requirement for autocrine prolactin, mammary glands from lactation-defective Akt1 -/-;Akt2 +/-mice failed to express autocrine prolactin or activate Stat5 during late pregnancy despite normal levels of circulating serum prolactin and pituitary prolactin production. Our findings reveal that PI3K-Akt pathway activation is necessary and sufficient to induce autocrine prolactin production in the mammary gland, Stat5 activation, and terminal mammary epithelial differentiation, even in the absence of the normal developmental program that prepares the mammary gland for lactation. Together, these findings identify a function for autocrine prolactin during normal development and demonstrate its endogenous regulation by the PI3K-Akt pathway.

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Section: Discussionmentioning

confidence: 99%

Autocrine prolactin induced by the Pten–Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways

et al. 2012

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“…Studies utilizing bromocriptine, which inhibits pituitary PRL synthesis, or pituitary isographs, which secrete large amounts of PRL, have established that endocrine PRL is largely responsible for PRL's reported physiological functions (Freeman et al, 2000). However, PRL is also synthesized in several extrapituitary sites, including mammary epithelial cells (Lkhider et al, 1996;Escalada et al, 1997;Iwasaka et al, 2000), raising the possibility that in addition to PRL's demonstrated direct and indirect endocrine roles, it may regulate mammopoiesis via an autocrine or paracrine mechanism. We addressed this question by comparing the development of transplanted mammary epithelium with and without a null mutation of the PRL gene, using the endpoints of morphology/histology, cell proliferation, and cell apoptosis.…”

Section: Mammary Prl Production Is Not Required For Normal Developmentioning

confidence: 99%

Investigation of the Transcriptional Changes Underlying Functional Defects in the Mammary Glands of Prolactin Receptor Knockout Mice

Ormandy

Naylor²,

Harris³

et al. 2003

Recent Progress in Hormone Research

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Knockout (KO) mice have been created that carry null mutations of genes encoding molecules essential for prolactin (PRL) release, PRL, the receptor for prolactin (PRLR), and various members of the receptor's signaling pathway. This allowed an in vivo genetic analysis of the role of PRL in target organ function. In PRLKO and PRLRKO mice, mammary ductal side branching was absent, terminal end bud (TEB)-like structures persisted at the ductal termini well into maturity, and no alveolar buds formed along the ductal tree. Transplants of recombined mammary glands formed from stromal and epithelial elements with and without PRLR showed normal development, while supplementation of progesterone levels in PRLKO animals restored ductal side branching. During pregnancy, PRLR heterozygous animals initially showed normal ductal and alveolar development. However, alveolar development stalled during late pregnancy, preventing successful lactation. This defect could be rescued by the loss of a single allele of the suppressor of cytokine signaling (SOCS) 1 gene. Transplants of recombined glands containing PRLRKO epithelium and wild-type (WT) stroma formed alveolar buds during pregnancy but showed no lobuloalveolar development. Recombinations of WT epithelium and PRLRKO stroma showed normal development, demonstrating that a direct action of the lactogenic hormones is confined to the epithelium, to promote lobuloalveolar development. Transcript profiling of epithelial transplants expressing or not expressing PRLR was used during early pregnancy to investigate the transcriptional response to lactogens underlying this defect. Such profiling has identified a number of genes with well-characterized roles in mammary development, in addition to a number of novel transcripts.

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“…Interestingly, PRL appears to not be expressed in the rat liver (Kurtz et al 1993), a tissue rich in PRLR (Bole-Feysot et al 1998). In rats, PRL mRNA is first expressed within the mammary gland at midlate pregnancy and is expressed throughout lactation (Iwasaka et al 2000). Along these lines, precocious lactogenesis in neonatally-estrogenized nulliparous female mice coincides with elevated expression of PRL mRNA in the mammary gland (Hovey et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Tissue-specific regulation of porcine prolactin receptor expression by estrogen, progesterone, and prolactin

Trott

Horigan

Gloviczki

et al. 2009

Journal of Endocrinology

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Prolactin (PRL) acts through its receptor (PRLR) via both endocrine and local paracrine/autocrine pathways to regulate biological processes including reproduction and lactation. We analyzed the tissue-and stage of gestationspecific regulation of PRL and PRLR expression in various tissues of pigs. Abundance of pPRLR-long form (LF) mRNA increased in the mammary gland and endometrium during gestation while in other tissues it remained constant. There was a parallel increase in the abundance of the pPRLR-LF protein in the mammary gland and endometrium during gestation. We determined the hormonal regulation of pPRLR-LF mRNA expression in various tissues from ovariectomized, hypoprolactinemic gilts given combinations of the replacement hormones estrogen (E 2 ), progestin (P), and/or haloperidol-induced PRL. Abundance of pPRLR-LF mRNA in kidney and liver was unaffected by hormone treatments. Expression of uterine pPRLR-LF mRNA was induced by E 2 whereas the effect of E 2 was abolished by co-administering P. The expression of pPRLR-LF mRNA in the mammary gland stroma was induced by PRL, whereas E 2 induced its expression in the epithelium. In contrast to these changes in pPRLR expression, pPRL expression was relatively constant and low during gestation in all tissues except the pituitary. Taken together, these data reveal that specific combinations of E 2 , P, and PRL differentially regulate pPRLR-LF expression in the endometrium and mammary glands, and that the action of PRL on its target tissues is dependent upon pPRLR-LF abundance more so than the local PRL expression.

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Expression of Prolactin mRNA in Rat Mammary Gland During Pregnancy and Lactation

Cited by 25 publications

References 29 publications

Autocrine prolactin induced by the Pten–Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways

Autocrine prolactin induced by the Pten–Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways

Investigation of the Transcriptional Changes Underlying Functional Defects in the Mammary Glands of Prolactin Receptor Knockout Mice

Tissue-specific regulation of porcine prolactin receptor expression by estrogen, progesterone, and prolactin

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