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.

Expression Pattern Implicates a Potential Role for Luman Recruitment Factor in the Process of Implantation in Uteri and Development of Preimplantation Embryos in Mice

“…Besides its cellular function, the biological role of LRF is largely unknown. Recently, we found a severe maternal behavioral defect in female LRF gene knockout mice accompanied by misregulation of glucocorticoid and prolactin signaling [23]. Our preliminary data also suggest a fertility deficit in these mutant mice (unpublished), suggesting a potential role for LRF in reproduction and related hormonal signaling.…”

A missense variant in CREBRF is associated with taller stature in Samoans

“…However, the function of CREBRF is minimally characterized, so the mechanisms by which rs373863828 affects these phenotypes are currently unclear. Individual studies have indicated that this transcription factor impacts glucocorticoid signaling, autophagy, unfolded protein response, and starvation resistance, as well as murine decidualization, embryo implantation, and maternal behavior (Audas, Li, Liang, & Lu, 2008; Li et al, 2016; Martyn et al, 2012; Minster et al, 2016; Xue et al, 2016; Yang et al, 2013). Future studies should aim to refine the effect of this variation on the related phenotypes of height, weight, and BMI in other Pacific Island populations, as well as other anthropometric traits.…”

A thrifty variant in CREBRF strongly influences body mass index in Samoans

“…The potential importance of this variant in organismal energy homeostasis is further supported by the ‘lean’ phenotype of mice 30 and flies 26 lacking the ortholog for this gene. These data, in combination with evidence of positive selection, support a thrifty variant hypothesis for human obesity and underscore the value of examining unique populations to identify new genetic contributions to complex traits.…”

“…In support of this hypothesis, expression of CREBRF orthologs is highly induced by starvation in all tissues of Drosophila 26,27 as well as in human lymphoblasts 28,29 . Moreover, REPTOR -knockout flies 26 and Crebrf -knockout mice 30 have lower total energy storage and body weight, respectively. Similarly, we found that nutrient starvation of 3T3-L1 preadipocytes rapidly increased Crebrf mRNA levels, which peaked by 4 h at levels 13-fold higher than those seen at 0 h ( P = 1.1 × 10 −16 ) and remained elevated by 5-fold at 24 h after the start of starvation ( P = 4.1 × 10 −14 ) (Fig.…”