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Cochlin, a Secreted von Willebrand Factor Type A Domain-Containing Factor, Is Regulated by Leukemia Inhibitory Factor in the Uterus at the Time of Embryo Implantation

Cancer and Developmental Biology Laboratory, National Cancer Institute, Division of Basic Science, National Cancer Institute at Frederick, Frederick, Maryland 21702

Address all correspondence and requests for reprints to: Colin L. Stewart, Building 539, Room 121, National Cancer Institute, Division of Basic Science, National Cancer Institute at Frederick, Frederick, Maryland 21702. E-mail: stewartc{at}ncifcrf.gov.

Embryo implantation is a required step in the reproduction of all mammals. In mice, a transient rise in the uterine expression of leukemia inhibitory factor (LIF) occurs on d 4 of pregnancy and is essential for embryo implantation. However, which genes are regulated by LIF in the uterus at implantation has not been determined. We performed a subtractive hybridization assay between luminal epithelial (LE) mRNAs from d 3 and 4 of pregnancy to find genes up-regulated on d 4 and which would be potentially regulated by LIF. One candidate, Coch-5b2, was up-regulated on the day of implantation. Coch mRNA localized to the LE of wild-type mice and was not detected in uteri from Lif-deficient mice. Treatment of LE with LIF, both in vitro and in vivo, resulted in the up-regulation of Coch. Coch is also highly expressed in other tissues, including the spleen and inner ear, but only in the uterus is Coch expression regulated by LIF. Mice were derived in which Coch was either deleted or tagged with a LacZ reporter. In mice carrying the tagged Coch gene, expression of Coch was detected in the LE and also at the site of embryo implantation. However, mice in which the Coch gene was deleted were normal, showing no overt defects in their reproduction. Although loss of Coch expression is not essential to reproduction in mice, it may serve as a useful marker for assessing the state of uterine receptivity in response to LIF at the onset of implantation.

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