Bone morphogenetic protein-4 acts as an ovarian follicle survival factor and promotes primordial follicle development
Bone morphogenetic protein-4 acts as an ovarian follicle survival factor and promotes primordial follicle development
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DOI：
10.1095/biolreprod.103.018671
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发表时间：
2003-10-01
影响因子：
3.6
通讯作者：
Skinner, MK
中科院分区：
文献类型：
--
作者：
Nilsson, EE;Skinner, MK
卵巢内卵泡的生长和发育高度依赖于自分泌和旁分泌信号，涉及来自颗粒细胞、卵泡膜细胞、基质间质细胞和卵母细胞的生长因子。在卵巢中检测到生长因子骨形态发生蛋白-4（BMP-4）及其受体（BMPR-IB），BMPR-IB的突变与异常排卵率有关。本研究的目的是研究BMP-4在原始卵泡发育早期阶段的作用。将4日龄大鼠卵巢置于全卵巢器官培养系统中培养2周，以研究外源性BMP-4处理对早期卵泡发育的影响。BMP-4处理的卵巢比未处理的对照组有显著更高比例的发育中的初级卵泡和更少的停滞的原始卵泡。这表明BMP-4促进原始卵泡发育和原始卵泡向初级卵泡的转变。还用针对BMP-4的中和抗体处理卵巢以确定去除内源性产生的BMP-4的效果。有趣的是，用BMP-4抗体处理的卵巢明显小于对照。这与卵母细胞和原始卵泡的进行性损失、细胞凋亡的进行性增加以及伴随的正常卵巢组织形态的损失有关。免疫细胞化学将BMP-4蛋白定位于分离的基质细胞群，选择的基质细胞（即，与发育中的原始卵泡和卵泡的基底膜有关的前囊细胞。用BMP-4处理卵巢，并在器官培养后收集RNA，以确定BMP-4信号传导是否影响其他生长因子的表达。试剂盒配体和碱性成纤维细胞生长因子的表达没有变化，但TGR α的表达下降，在整个卵巢。综上所述，这些数据表明，BMP-4在促进新生儿卵巢原始卵泡的存活和发育中起着重要作用。
The growth and development of follicles within the ovary are highly dependent on autocrine and paracrine signaling involving growth factors from granulosa cells, theca cells, stromal interstitial cells, and the oocytes. The growth factor bone morphogenetic protein-4 (BMP-4) and its receptor (BMPR-IB) have been detected in ovaries, and a mutation in BMPR-IB has been associated with abnormal ovulation rate. The objective of the current study was to examine the role that BMP-4 plays in the early stages of primordial follicle development. Ovaries from 4-day-old rats were placed into a whole-ovary organ culture system for 2 wk to investigate the effect that treatment with exogenous BMP-4 has on early follicle development. BMP-4-treated ovaries had a significantly higher proportion of developing primary follicles and fewer arrested primordial follicles than did untreated controls. This indicates that BMP-4 promotes primordial follicle development and the primordial-to-primary follicle transition. Ovaries were also treated with neutralizing antibody against BMP-4 to determine effects of removing endogenously produced BMP-4. Interestingly, ovaries treated with BMP-4 antibody were markedly smaller than controls. This was associated with a progressive loss of oocytes and primordial follicles, a progressive increase in cellular apoptosis, and an accompanying loss of normal ovarian tissue morphology over time. Immunocytochemistry localized BMP-4 protein to isolated stromal cell populations, selected stromal cells (i.e., pretheca cells) associated with developing primordial follicles, and the basement membrane of follicles. Ovaries were treated with BMP-4 and RNA collected after organ culture to determine whether BMP-4 signaling affects expression of other growth factors. Kit ligand and basic fibroblast growth factor expression was unchanged, but TGRalpha expression was decreased in whole ovaries. Taken together, these data suggest that BMP-4 plays an important role in promoting the survival and development of primordial follicles in the neonatal ovary.