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The Cell-Surface Isoform of Colony Stimulating Factor 1 (CSF1) Restores but Does Not Completely Normalize Fecundity in CSF1-Deficient Mice¹

Section of Comparative Medicine,⁵ Department of Internal Medicine,⁶ Yale University School of Medicine, New Haven, Connecticut 06520

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.

gene regulation, growth factors, pregnancy, sperm motility and transport, uterus

¹ Supported by grants from the National Institutes of Health DK45228, DE12459 (to K.L.I.), and, in part, by the Yale Core Center for Musculoskeletal Disorders P30 AR46032.

² Correspondence: Gang-Qing Yao, Section of Comparative Medicine, Yale University School of Medicine, P.O. Box 208016, New Haven, CT 06520-8016. FAX: 203 785 7499; gang-qing.yao{at}yale.edu

³ These authors contributed equally to this work.

⁴ Current address: National Institute of Biotechnology in the Negev, P.O.Box 653, Ben-Gurion University of the Negev, Beer-Sheva, Israel, 84105.