Ovadia Shira, Insogna Karl, Yao Gang-Qing
Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Biol Reprod. 2006 Feb;74(2):331-6. doi: 10.1095/biolreprod.105.045047. Epub 2005 Oct 19.
The complete genetic absence of colony stimulating factor 1 (CSF1) in CSF1-deficient Csf1(op)/Csf1(op) mice leads to reproductive defects in males and females. Although the cell-surface or membrane-bound isoform of CSF1 (mCSF1) is biologically active in bone, little is known about its role in reproduction. Transgenic mice expressing mCSF1 under the control of the 2.4-kb rat collagen type I alpha promoter were developed [Tg(Col1a1-mCSF1)1Gqy] and bred onto a Csf1(op)/Csf1(op) background [Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy] to examine the effects of the mCSF1 isoform in bone in vivo. Surprisingly, when interbred, these mice were fertile. The Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy transgenic male mice have normal libido, sperm number and percent of motile sperm. In Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy females, puberty and estrus cycles are at expected age and duration. Further, females are able to carry pregnancies to term and nurse their offspring. Crosses of Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy males or females with their control littermates showed no significant differences in either number or viability of offspring. However, crossing Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy males with Csf1(op); Tg(Col1a1-mCSF1)1Gqy females resulted in a decline in both the number and viability of offspring, suggesting that a subtle reproductive defect might persist in the transgenic animals that was only manifest when the animals were interbred. Although the gravid murine uterus expresses extremely high levels of CSF1 that are thought to be important for reproduction, uterine tissue levels of CSF1 remained low and unchanged during pregnancy in Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy mice. Low levels of CSF1 protein were detected in serum and in lung and uterine tissue in Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy mouse, which likely result from the known proteolytic shedding of mCSF1 from the cell surface. These data are consistent with the conclusion that mCSF1, when shed from the cell surface, can support reproduction and that high uterine tissue levels of CSF1 may not be required for mouse reproduction.
在集落刺激因子1缺陷型（Csf1(op)/Csf1(op)）小鼠中，集落刺激因子1（CSF1）完全缺失会导致雄性和雌性出现生殖缺陷。尽管CSF1的细胞表面或膜结合亚型（mCSF1）在骨骼中具有生物学活性，但其在生殖中的作用却鲜为人知。构建了在2.4 kb大鼠I型胶原α启动子控制下表达mCSF1的转基因小鼠【Tg(Col1a1-mCSF1)1Gqy】，并将其培育到Csf1(op)/Csf1(op)背景【Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy】上，以研究mCSF1亚型在体内骨骼中的作用。令人惊讶的是，这些小鼠杂交时是可育的。Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy转基因雄性小鼠具有正常的性欲、精子数量和活动精子百分比。在Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy雌性小鼠中，青春期和发情周期的年龄及持续时间均正常。此外，雌性能够怀孕至足月并哺育后代。Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy雄性或雌性小鼠与其对照同窝小鼠杂交，后代数量和活力均无显著差异。然而，将Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy雄性小鼠与Csf1(op); Tg(Col1a1-mCSF1)1Gqy雌性小鼠杂交，后代数量和活力均下降，这表明转基因动物可能存在一种细微的生殖缺陷，只有在动物杂交时才会显现出来。尽管妊娠小鼠子宫中表达极高水平的CSF1，而这被认为对生殖很重要，但在Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy小鼠的孕期中，子宫组织中的CSF1水平仍保持较低且无变化。在Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy小鼠的血清、肺和子宫组织中检测到低水平的CSF1蛋白，这可能是由于已知的mCSF1从细胞表面的蛋白水解脱落所致。这些数据与以下结论一致：mCSF1从细胞表面脱落时可以支持生殖，并且小鼠生殖可能不需要子宫组织中高水平的CSF1。
