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The cell-surface isoform of colony stimulating factor 1 (CSF1) restores but does not completely normalize fecundity
Shira Ovadia1, Karl Insogna, Gang-Qing Yao
1Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Abstract:
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.
Insights
The membrane-bound form of colony stimulating factor 1 (mCSF1) can support reproduction in mice lacking CSF1. This suggests high uterine CSF1 levels may not be essential for successful mouse reproduction.
Area of Science:
- Reproductive biology
- Molecular endocrinology
- Genetics
Background:
- Colony stimulating factor 1 (CSF1) is crucial for reproduction, with its absence causing defects.
- The role of the membrane-bound isoform of CSF1 (mCSF1) in reproduction is largely unknown.
- CSF1-deficient mice (Csf1(op)/Csf1(op)) exhibit reproductive impairments.
Purpose of the Study:
- To investigate the reproductive function of the membrane-bound CSF1 (mCSF1) isoform in vivo.
- To determine if mCSF1 expression can rescue reproductive defects in CSF1-deficient mice.
- To explore the necessity of high uterine CSF1 levels for mouse reproduction.
Main Methods:
- Generation of transgenic mice expressing mCSF1 under the collagen type I alpha promoter [Tg(Col1a1-mCSF1)1Gqy].
- Breeding transgenic mice onto a CSF1-deficient Csf1(op)/Csf1(op) background.
- Assessment of reproductive parameters including fertility, sperm characteristics, estrus cycles, pregnancy, and offspring viability.
Main Results:
- Transgenic Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy mice were fertile with normal male and female reproductive functions.
- Offspring number and viability were comparable to controls when crossed with control littermates.
- A subtle reproductive defect was observed when transgenic mice were interbred, indicated by reduced offspring number and viability.
- Low CSF1 protein levels were detected in serum and tissues, consistent with mCSF1 shedding, despite normal reproduction.
Conclusions:
- The cell-surface or membrane-bound CSF1 isoform (mCSF1), when shed, can support mouse reproduction.
- High uterine tissue levels of CSF1 may not be strictly required for successful mouse reproduction.
- Further research is needed to elucidate the subtle reproductive defect observed in interbred transgenic mice.
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