Fertility impairment in granulocyte-macrophage colony-stimulating factor-deficient mice
Fertility impairment in granulocyte-macrophage colony-stimulating factor-deficient mice
复制标题
DOI：
10.1095/biolreprod60.2.251
复制
发表时间：
1999-02-01
影响因子：
3.6
通讯作者：
Seamark, RF
中科院分区：
文献类型：
--
作者：
Robertson, SA;Roberts, CT;Seamark, RF
粒细胞-巨噬细胞集落刺激因子(GMCSF)被认为是女性生殖道细胞间通讯的重要介质，其主要靶细胞是周期和妊娠子宫、植入前胚胎和发育中的胎盘滋养层细胞中的大量髓系白细胞。为了确定这种细胞因子在生殖中的生理意义，我们检测了GM-CSF基因缺陷(GM-/-)小鼠的生育力。GM-/-小鼠的着床率是正常的，并产生了存活的幼鼠。然而，由于胚胎在妊娠晚期和出生后早期死亡，GM-/-x GM-/-配对在断奶时的平均产仔数比GM+/-x GM+/-配对小25%，其中雄性幼崽的损失不成比例。在怀孕第17天，GM-/-孕妇吸收和畸形胎儿的平均数量是GM+/-女性的两倍(21%，GM+/-女性为11%)；存活胚胎的平均胎儿体重和平均胎儿/胎盘比例分别减少7%和6%；极小胎儿(<；500 mg)的数量是后者的9倍(23%对2.5%)。在出生后的前3周，转基因母亲所生幼崽的死亡率是后者的4.5倍(9%，而转基因+/-雌性为2%)，而且转基因/转基因幼崽，尤其是雄性幼崽，体型变小一直持续到成年。当GM-/-雌性与GM+/+雄性交配时，母体GM-CSF缺乏的有害影响不那么明显；出生时和断奶时的产仔数并不明显小于GM+/-交配，胎儿体重和胎儿/胎盘比率也是相似的。当用聚合酶链式反应对杂合子配对中的胚胎组织进行分型时，发现来自GM-/-雌性的GM-/-胎儿比它们的GM+/-胎小，也比GM+/-雌性妊娠的GM-/-胎儿小。在发情周期、妊娠早期和中期，子宫颗粒细胞和巨噬细胞群的大小和分布是正常的。胎盘结构分析显示，GM-/-胎盘迷路/海绵滋养层面积比减少约28%，海绵滋养层中空泡化滋养层“糖原细胞”比例减少。因此，由于微小的发育异常导致的胎盘功能受损可能是GM-CSF缺陷小鼠胚胎生长迟缓的部分原因。总而言之，这些研究表明，在缺乏母体GM-CSF的情况下，胎儿的生长和生存能力受到威胁。当胚胎也缺乏GM-CSF时，有害影响最为明显，这表明母体或胎儿来源的GM-CSF对于小鼠胎儿的最佳生长和存活是必需的。
Granulocyte-macrophage colony-stimulating factor (GMCSF) has been identified as a potentially important mediator of intercellular communication in the female reproductive tract, with principal target cells being the large populations of myeloid leukocytes in the cycling and pregnant uterus, the preimplantation embryo, and trophoblast cells of the developing placenta. To determine the physiological significance of this cytokine in reproduction, the fertility of genetically GM-CSF-deficient (GM-/-) mice was examined. Implantation rates were normal in GM-/- mice, and viable pups were produced. However, the mean litter sizes of GM-/- x GM-/- breeding pairs were 25% smaller at weaning than those of GM+/- x GM+/- pairs, due to fetal death late in gestation and early in postnatal life, with a disproportionate loss of male pups. On Day 17 of pregnancy, the mean number of resorbing and malformed fetuses was twice as high in pregnant GM-/- females (21%, vs. 11% in GM+/- females); the mean fetal weight and the mean fetal:placental ratio in surviving conceptuses were diminished by 7% and 6%, respectively; and the number of very small fetuses (< 500 mg) was 9-times as high (23% vs. 2.5%). Mortality during the first 3 wk of life was 4.5-times as high in pups born to GM-/- mothers (9%, vs. 2% in GM+/- females), and diminished size persisted in GM-/- pups, particularly males, into adulthood. The detrimental effect of maternal GM-CSF deficiency was less apparent when GM-/- females were mated with GM+/+ males; litter sizes at birth and at weaning were not significantly smaller than in GM+/- matings, and fetal weights and fetal:placental ratios were also comparable. When polymerase chain reaction was used to genotype embryonic tissue in heterozygote matings, GM-/- fetuses from GM-/- females were found to be smaller than their GM+/- littermates and smaller than GM-/- fetuses gestated in GM+/- females. The size and distribution of uterine granulocyte and macrophage populations were normal during the estrous cycle, during early pregnancy, and in midgestation. Analysis of placental structure revealed that the ratio of labyrinthine to spongiotrophoblast areas was reduced by approximately 28% in GM-/- placentae, and the proportion of vacuolated trophoblast "glycogen cells" in the spongiotrophoblast layer was diminished. Compromised placental function as a result of subtle developmental aberrations may therefore partially account for embryonic growth retardation in GM-CSF-deficient mice. Collectively, these studies show that fetal growth and viability are jeopardized in the absence of maternal GM-CSF. The detrimental effects are most clearly evident when the conceptus is also GM-CSF deficient, suggesting that GM-CSF of either maternal or fetal origin is required for optimal growth and survival of the fetus in mice.