Prolactin signaling through the short isoform of the mouse prolactin receptor regulates DNA binding of specific transcription factors, often with opposite effects in different reproductive issues

In 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.We 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.Our 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.PRL is a polypeptide hormone known to exert a great number of biological functions by regulating transcription of genes involved in several physiological pathways [rev in [1]]. PRL relays its effect by binding to specific receptors (PRL-R) and activating intracellular signaling molecules. The PRL-R belongs to type I transmembrane receptor family and structurally resembles the class I cytokine receptor superfamily [rev in [2]]. Multiple isoforms of membrane-bound PRL-R, resulting from alternative splicing of the primary transcript, have been identified in several species [3-5]. The two major PRL-R isoforms described in rodents are the short (PRL-RS) and long (PRL-RL) forms. These different PRL-R isoforms share a common extracellular domain, but differ in the length and composition of the