Trends in Endocrinology & Metabolism
ReviewThe prolactin family: effectors of pregnancy-dependent adaptations
Introduction
Prolactin (PRL) is a hormone and cytokine with a long history, ranging from its discovery over 75 years ago 1, 2, 3 to its noted involvement in a diversity of vertebrate biological functions [4]. Numerous excellent reviews have been written on the structure of PRL, its receptor and its involvement in the biology of various organisms 5, 6, 7, 8, 9, 10, 11, 12. A less well appreciated role for PRL or, more specifically, the ancestral Prl gene, is as an evolutionary template for the generation of new genes, encoding proteins with a breadth of actions. The birth of these new genes is linked to viviparity but is not a common feature of all viviparous species. Collectively, Prl and the Prl-related genes are referred to as members of the PRL family. Knowledge about the PRL family grows as the genomes of different species are sequenced and characterized. Thus far, it is evident that the mouse and rat represent species where the PRL gene family has undergone a particularly robust expansion 13, 14, 15. Insights into the significance of the PRL family expansion have recently been derived from mutational analysis of the mouse 16, 17.
Here, we discuss the biology of PRL family gene expansion and provide evidence that members of the PRL family are effectors of pregnancy-dependent adaptations to physiological stressors. Our focus is on the PRL family of the mouse and rat.
Section snippets
Mouse and rat expanded PRL families
Discovery of the expanded PRL family started early in the previous century, during the formative stages of the discipline of endocrinology (Box 1). Awareness of protein families related to PRL within the mouse and rat grew as technical breakthroughs in protein purification, cDNA cloning and genome analyses were having an impact on biomedical investigation. For the majority of expanded PRL family members, gene discovery was not driven by prior biological characterization of the ligand.
PRL family gene expression and viviparity
The PRL family is linked to pregnancy. PRL family gene expression involves the coordination of maternal, extraembryonic and fetal tissues, and spans the entire duration of pregnancy [25] (Box 3).
The anterior pituitary, uterine decidua and placenta are sources of PRL family ligands (Table 1). At the initiation of pregnancy, mating activates a neuroendocrine response, resulting in twice-daily surges of PRL from the anterior pituitary [26]. These surges of PRL continue for the first half of
Biology of the PRL family
Biological activities of PRL family ligands can be categorized as classical and nonclassical [22]. Classical actions are mediated by ligand interactions with the PRL receptor, and nonclassical modes of action use other signaling pathways.
Roles for the PRL family in adaptations to physiological stressors
Mouse mutagenesis has been used as a tool to discover the involvement of the PRL family in adaptations to physiological stressors. Four lines of mutant mice have been generated: one with a null mutation in the Prl gene [33], the second with a gain of function mutation resulting in the constitutive expression of PLP-E [72] and the third and fourth lines with null mutations in the Prlpa gene [16] and Dtprp gene [17], respectively.
Conclusions and future directions
Expansion of the mouse and rat PRL families did not occur in a controlled laboratory setting, in which nutrition and temperature are carefully regulated and exposure to pathogens limited. Instead, the expanded PRL gene family probably provided the mouse and rat with selective advantages for surviving in more hostile conditions. A ‘proof of principle’ has been established that members of the expanded PRL family are biologically relevant. Gene-targeting strategies need to be extended to the
Acknowledgements
Reviews have been cited, where possible, instead of an exhaustive list of primary research reports. Consequently, we apologize to scientists who have contributed to research on the biology of the PRL family and whose work has not been cited. Research from our laboratory is supported by grants from the National Institutes of Health (HD20676, HD39878, HD48861, HD49503) and the Hall Family Foundation. We would like to acknowledge current and former members of our laboratory for their valuable
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