Li Dan, Ji Yan, Zhao Chunlan, Yao Yapeng, Yang Anlan, Jin Honghong, Chen Yang, San Mingjun, Zhang Jing, Zhang Mingjiao, Zhang Luqing, Feng Xuechao, Zheng Yaowu
Transgenic Research Center, Northeast Normal University, Changchun, Jilin, China.
Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Endocrinol. 2018 Nov;239(2):121-136. doi: 10.1530/JOE-18-0356.
Oxytocin receptor (OXTR) is a G-protein-coupled receptor and known for regulation of maternal and social behaviors. Null mutation (Oxtr-/-) leads to defects in lactation due to impaired milk ejection and maternal nurturing. Overexpression of OXTR has never been studied. To define the functions of OXTR overexpression, a transgenic mouse model that overexpresses mouse Oxtr under β-actin promoter was developed ( ++ Oxtr). ++ Oxtr mice displayed advanced development and maturation of mammary gland, including ductal distention, enhanced secretory differentiation and early milk production at non-pregnancy and early pregnancy. However, ++ Oxtr dams failed to produce adequate amount of milk and led to lethality of newborns due to early involution of mammary gland in lactation. Mammary gland transplantation results indicated the abnormal mammary gland development was mainly from hormonal changes in ++Oxtr mice but not from OXTR overexpression in mammary gland. Elevated OXTR expression increased prolactin-induced phosphorylation and nuclear localization of STAT5 (p-STAT5), and decreased progesterone level, leading to early milk production in non-pregnant and early pregnant females, whereas low prolactin and STAT5 activation in lactation led to insufficient milk production. Progesterone treatment reversed the OXTR-induced accelerated mammary gland development by inhibition of prolactin/p-STAT5 pathway. Prolactin administration rescued lactation deficiency through STAT5 activation. Progesterone plays a negative role in OXTR-regulated prolactin/p-STAT5 pathways. The study provides evidence that OXTR overexpression induces abnormal mammary gland development through progesterone and prolactin-regulated p-STAT5 pathway.
催产素受体（OXTR）是一种G蛋白偶联受体，以调节母体行为和社会行为而闻名。无效突变（Oxtr-/-）会导致泌乳缺陷，因为乳汁排出和母体哺育功能受损。OXTR的过表达尚未得到研究。为了确定OXTR过表达的功能，构建了一种在β-肌动蛋白启动子下过表达小鼠Oxtr的转基因小鼠模型（++Oxtr）。++Oxtr小鼠的乳腺显示出提前发育和成熟，包括导管扩张、分泌分化增强以及在非孕期和孕早期提前产奶。然而，++Oxtr母鼠未能产生足够的乳汁，并且由于泌乳期乳腺的早期退化导致新生小鼠死亡。乳腺移植结果表明，异常的乳腺发育主要源于++Oxtr小鼠体内的激素变化，而非乳腺中OXTR的过表达。OXTR表达升高会增加催乳素诱导的STAT5磷酸化和核定位（p-STAT5），并降低孕酮水平，导致非孕期和孕早期雌性小鼠提前产奶，而泌乳期催乳素和STAT5激活水平低则导致产奶不足。孕酮处理通过抑制催乳素/p-STAT5途径逆转了OXTR诱导的乳腺加速发育。催乳素给药通过激活STAT5挽救了泌乳缺陷。孕酮在OXTR调节的催乳素/p-STAT5途径中起负作用。该研究提供了证据，证明OXTR过表达通过孕酮和催乳素调节的p-STAT5途径诱导异常乳腺发育。
