Luman/CREB3 Recruitment Factor Regulates Glucocorticoid Receptor Activity and Is Essential for Prolactin-Mediated Maternal Instinct

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis is a major part of the neuroendocrine system in animal responses to stress. It is known that the HPA axis is attenuated at parturition to prevent detrimental effects of glucocorticoid secretion including inhibition of lactation and maternal responsiveness. Luman/CREB3 recruitment factor (LRF) was identified as a negative regulator of CREB3 which is involved in the endoplasmic reticulum stress response. Here, we report a LRF gene knockout mouse line that has a severe maternal behavioral defect. LRF^−/− females lacked the instinct to tend pups; 80% of their litters died within 24 h, while most pups survived if cross-fostered. Prolactin levels were significantly repressed in lactating LRF^−/− dams, with glucocorticoid receptor (GR) signaling markedly augmented. In cell culture, LRF repressed transcriptional activity of GR and promoted its protein degradation. LRF was found to colocalize with the known GR repressor, RIP140/NRIP1, which inhibits the activity by GR within specific nuclear punctates that are similar to LRF nuclear bodies. Furthermore, administration of prolactin or the GR antagonist RU486 restored maternal responses in mutant females. We thus postulate that LRF plays a critical role in the attenuation of the HPA axis through repression of glucocorticoid stress signaling during parturition and the postpartum period.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01142-12.

ACKNOWLEDGMENTS

This work was supported by the Canadian Institutes for Health Research (MOP53186) and Natural Sciences and Engineering Research Council of Canada (238950-06).

We thank the Central Animal Facility at the University of Guelph. We thank Andrew Bendall, Timothy Audas, Yaping Jin, Cheryl Cragg, Graham Smith, Amy Clipperton Allen, Anna Phan, Jennifer Brisbin, Melanie Wills, Adam McCluggage, and Alyssa Lima, who helped with data collection, provided technical assistance, and/or contributed conceptually to the project. We thank Johanna Zilliacus for pEGFP-RIP140, Ronald Evans for pMMTV-Luc, and Jorma Palvimo for pSG5-hGR plasmids.