The Discovery of Uteroglobin and Its Significance for Reproductive Biology and Endocrinology

Abstract

The discovery of uteroglobin resulted from investigations on the biochemical composition of oviductal and uterine secretions of the rabbit and other mammals. These determinations about physiological composition were urgently requested to prepare culture media for research on early mammalian development in vitro. Discovery of significant proteins during the sixties reflected the laboratory skills of that time. Protein characterization was achieved by isolation via Sephadex gels, electrophoresis on polyacrylamide gels, and finally immunoprecipitation using classical polyclonal antibodies. The molecular biology was not yet established. Uteroglobin could be found as the major protein component of rabbit uterine secretion. From the beginning, it was already identified as an unusually small, spheric uterine secretory molecule without any carbohydrates‐hence its name. Uteroglobin was the first mammalian protein that turned out to be progesterone‐regulated and, at the same time, released in mg amounts actually in one organ compartment. Moreover, uteroglobin and its gene proved to be a reliable model for the description of progesterone/progesterone receptor complex action at the DNA level. After its original observation in the uterus, however, uteroglobin was detected also in several other organs, for example, the epididymis, the seminal vesicle, and the lung. Initially, it could not be found in the blood, which challenged the hypothesis that uteroglobin specifically should operate by local activation rather than by a humoral or endocrine effect. Later, though, the human uteroglobin molecule, isolated from blood filtrate, was used for detailed structural analyses. The rabbit uteroglobin model certainly was beneficial for reproductive biological research. Experimental interference with steroid hormone regulation during preimplantation presented surprising effects, which led to the discovery of the transposition of the implantation window. The uterine secretion protein patterns, in particular the uteroglobin fraction and the β‐glycoprotein fraction, served as decisive marker profiles to identify the biological stage of the intrauterine microenvironment during preimplantation. This diagnostic procedure, using only protein parameters, enabled us to precisely predict the receptive stage of the endometrium for donated blastocysts to achieve implantation successfully.

Immunohistochemical and histochemical identification of proteins and carbohydrates in the equine endometrium: Reaction patterns in the cycling mare

“…In contrast to uterine secretions which showed highest levels of UGL during interestrus (Beier-Hellwig et al 1995), a maximal peak of intracellular UGL were detectable at estrus by immunohistochemistry. However it remains unclear if this accumulated UGL is being released into the uterine lumen or if it reflects an estrogen induced intraepithelial accumulation (Beier 2000). Nevertheless, the apical intracellular distribution and the positively stained material in the lumina of the glands, both detectable during interestrus, possibly correspond to a release of proteins from secretory vesicles of uterine glands.…”

Changes in major proteins in the embryonic capsule during immobilization (fixation) of the conceptus in the third week of pregnancy in the mare

“…4) was identified as uteroglobin/CCSP (Beier 2000) by immunoblotting with anti-rat-CCSP antibody (Fig. 10).…”

“…A similar situation was noted for uteroglobin that was always plentiful in the uterine lavage fluids but present in the yolk-sac fluid only before fixation. Uteroglobin/CCSP has a phospholipid-binding pocket (Beier 2000, von der Decken et al 2005 and it may also serve some role in the delivery of lipid ligands through the capsular glycan in the horse. Uteroglobin is a progesterone-dependent uterine secretory protein in various mammals including those in which the conceptus is not encapsulated (Beier 2000), and the abundant uteroglobin did not bind to the capsule.…”

“…Selective binding of some proteins to the capsule supports the concept that the capsule is like a 'mailbox' for delivery of various substances required by the embryo (Herrler et al , 2000b. For example, maternal p19/uterocalin binds to the capsule but is implicated mainly in delivery of lipids to the equine conceptus (Stewart et al 1995, 2000, Crossett et al 1996, Suire et al 2001. Equine yolk-sac wall tissues before fixation express unusually large amounts of the GM2-activator protein (GM2AP) implicated in transport and catabolism of glycolipids (Quinn et al 2006).…”

Rabbit as a reproductive model for human health

“…The size of the genital tract facilitated seminal landmark investigations on the endocrine and paracrine regulation of embryo-maternal interactions and uterine receptivity in early pregnancy and on hormone responsiveness of endometrial secretion, as highlighted by progesterone-regulated uteroglobin (Beier 1968(Beier , 2000. Recently, it was shown that the rabbit is a good model for Asherman's syndrome, or uterine synechia, defined as a partial or complete obliteration of the uterine cavity and/ or the cervical canal, and which can cause infertility and recurrent pregnancy losses (Fernandez H, Krouf M, Morel O, Ali MH & Chavatte-Palmer P, unpublished observations).…”