Abstract
BackgroundIt has been well established that prolactin (PRL) signals through the long form of its receptor (PRL-RL) and activates the Jak/Stat pathway for transcription of PRL target genes. However, signaling pathways mediated through the short PRL-R isoform (PRL-RS) remains controversial. Our recent finding that PRL signaling through PRL-RS represses two transcription factors critical for follicular development lead us to examine other putative PRL/PRL-RS target transcription factors in the decidua and ovary, two well-known target tissues of PRL action in reproduction.MethodsIn this investigation we used mice expressing PRL-RS on a PRL-R knockout background and a combo protein/DNA array to study the transcription factors regulated by PRL through PRL-RS only.ResultsWe show that PRL activation of the PRL-RS receptor either stimulates or inhibits the DNA binding activity of a substantial number of transcription factors in the decidua as well as ovary. We found few transcription factors to be similarly regulated in both tissues, while most transcription factors are oppositely regulated by PRL in the decidua and ovary. In addition, some transcription factors are regulated by PRL only in the ovary or only in the decidua. Several of these transcription factors are involved in physiological pathways known to be regulated by PRL while others are novel.ConclusionOur results clearly indicate that PRL does signal through PRL-RS in the decidua as well as the ovary, independently of PRL-RL, and activates/represses transcription factors in a tissue specific manner. This is the first report showing PRL/PRL-RS regulation of specific transcription factors. Many of these transcription factors were not previously known to be PRL targets, suggesting novel physiological roles for this hormone.
Highlights
It has been well established that prolactin (PRL) signals through the long form of its receptor (PRL-RL) and activates the Jak/Stat pathway for transcription of PRL target genes
It was thought that PRL does not signal though PRL-R isoform (PRL-RS) and that this receptor serves as a dominant negative to PRL-RL, since it lacks the cytoplasmic domain required for association with signaling molecules, such as the Stat transcription factors [9,10,11]
Regulation of Transcription factor activities by PRL in the ovary and decidua of transgenic mice expressing PRL-RS To determine the downstream signaling pathways of PRL/ PRL-RS, we examined the activities of transcription factors in the ovary and decidua of PRL-RS expressing mice using the TranSignal protein/DNA array
Summary
It has been well established that prolactin (PRL) signals through the long form of its receptor (PRL-RL) and activates the Jak/Stat pathway for transcription of PRL target genes. The two major PRL-R isoforms described in rodents are the short (PRL-RS) and long (PRL-RL) forms. Well-known targets of activated Jak include the Stat transcription factors, which are primary signaling mediators of PRL action [1,7]. It was thought that PRL does not signal though PRL-RS and that this receptor serves as a dominant negative to PRL-RL, since it lacks the cytoplasmic domain required for association with signaling molecules, such as the Stat transcription factors [9,10,11]. We have demonstrated both in vivo and in vitro [12,13], that PRL signaling through PRL-RS represses the activity of two transcription factors leading to inhibition in the activity of genes essential for normal follicular development
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