Fabre S, Pierre A, Pisselet C, Mulsant P, Lecerf F, Pohl J, Monget P, Monniaux D
INRA, Physiologie de la Reproduction et des Comportements, UMR 6073 INRA-CNRS-Université François Rabelais, 37380 Nouzilly, France.
J Endocrinol. 2003 Jun;177(3):435-44. doi: 10.1677/joe.0.1770435.
The hyperprolificacy phenotype of Booroola ewes is due to the presence of the FecB(B) allele at the FecB locus, recently identified as a single amino acid substitution (Q249R) in the bone morphogenetic protein (BMP) type-IB receptor (BMPR1B), and is associated with a more precocious differentiation of ovarian granulosa cells (GCs). To evaluate the consequences of the Booroola mutation on BMPR1B functions, the action of ligands of the transforming growth factor-beta (TGFbeta)/BMP family that act through (growth and differentiation factor-5, BMP-4) or independently of (activin A, TGFbeta-1) BMPR1B were studied on primary cultures of GCs from homozygous FecB(+) and FecB(B) ewes. All the tested TGFbeta/BMP family ligands inhibited progesterone secretion by FecB(+) GCs. Those inhibitory effects were lower for GCs from preovulatory (5-7 mm diameter) than from small antral follicles (1-3 mm diameter). The presence of the Booroola mutation was associated with a 3- to 4-fold (P<0.001) decreased responsiveness of GCs from FecB(B) compared with FecB(+) small follicles to the action of BMPR1B ligands. In contrast, TGFbeta-1 and activin A had similar inhibitory effects on progesterone secretion by GCs from FecB(+) and FecB(B) small follicles. No difference between genotypes was observed with GCs from preovulatory follicles. In transfection experiments with HEK-293 cells, co-expression of FecB(+) BMPR1B and BMPR2 resulted in a 2.6-fold (P<0.01) induction of the activity of a BMP-specific luciferase reporter construct by BMP-4. Interestingly, no response to BMP-4 was observed when cells were transfected with the FecB(B) form of the BMPR1B receptor. Overall, these data strongly suggest that the Q249R mutation is associated with a specific alteration of BMPR1B signaling in hyperprolific Booroola ewes.
波拉母羊的高产表型是由于在骨形态发生蛋白（BMP）IB型受体（BMPR1B）的FecB位点存在FecB（B）等位基因，该等位基因最近被鉴定为单个氨基酸替换（Q249R），并且与卵巢颗粒细胞（GCs）更早的分化有关。为了评估波拉突变对BMPR1B功能的影响，研究了通过（生长分化因子-5、BMP-4）或独立于（激活素A、转化生长因子-β1）BMPR1B起作用的转化生长因子-β（TGFβ）/BMP家族配体对来自纯合FecB（+）和FecB（B）母羊的GCs原代培养物的作用。所有测试的TGFβ/BMP家族配体均抑制FecB（+）GCs分泌孕酮。对于排卵前（直径5 - 7毫米）卵泡的GCs，这些抑制作用低于小腔卵泡（直径1 - 3毫米）的GCs。与FecB（+）小卵泡相比，波拉突变的存在使FecB（B）小卵泡的GCs对BMPR1B配体作用的反应性降低了3至4倍（P<0.001）。相反，转化生长因子-β1和激活素A对FecB（+）和FecB（B）小卵泡的GCs分泌孕酮具有相似的抑制作用。排卵前卵泡的GCs在基因型之间未观察到差异。在HEK - 293细胞的转染实验中，FecB（+）BMPR1B与BMPR2共表达导致BMP - 4对BMP特异性荧光素酶报告构建体的活性诱导增加2.6倍（P<0.01）。有趣的是，当用BMPR1B受体的FecB（B）形式转染细胞时，未观察到对BMP - 4的反应。总体而言，这些数据强烈表明，Q249R突变与高产波拉母羊中BMPR1B信号传导的特定改变有关。
