Luman/CREB3 Recruitment Factor Regulates Glucocorticoid Receptor Activity and Is Essential for Prolactin-Mediated Maternal Instinct
Luman/CREB3 Recruitment Factor Regulates Glucocorticoid Receptor Activity and Is Essential for Prolactin-Mediated Maternal Instinct
复制标题
DOI：
10.1128/mcb.01142-12
复制
发表时间：
2012-12-01
影响因子：
5.3
通讯作者：
Lu, Ray
中科院分区：
文献类型：
--
作者：
Martyn, Amanda C.;Choleris, Elena;Lu, Ray
下丘脑-垂体-肾上腺（HPA）轴是动物应激反应中神经内分泌系统的重要组成部分。已知HPA轴在分娩时减弱以防止糖皮质激素分泌的有害作用，包括抑制泌乳和母体反应。Luman/CREB 3募集因子（LRF）被确定为CREB 3的负调节因子，CREB 3参与内质网应激反应。在这里，我们报告了一个LRF基因敲除小鼠品系，有严重的母性行为缺陷。LRF-/-雌性缺乏照顾幼崽的本能; 80%的幼崽在24小时内死亡，而如果交叉寄养，大多数幼崽都能存活。泌乳期LRF-/-母鼠的催乳素水平显著受到抑制，糖皮质激素受体（GR）信号显著增强。在细胞培养中，LRF抑制GR的转录活性并促进其蛋白质降解。发现LRF与已知的GR阻遏物RIP 140/NRIP 1共定位，所述GR阻遏物RIP 140/NRIP 1抑制GR在与LRF核体相似的特定核点内的活性。此外，催乳素或GR拮抗剂RU 486的管理恢复突变体女性的母体反应。因此，我们推测，LRF通过抑制糖皮质激素应激信号在分娩和产后期间的HPA轴的衰减中起着至关重要的作用。
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.