Pregnancy-specific glycoproteins: evolution, expression, functions and disease associations

Abstract

Pregnancy-specific glycoproteins (PSGs) are members of the immunoglobulin superfamily and are closely related to the predominantly membrane-bound CEACAM proteins. PSGs are produced by placental trophoblasts and secreted into the maternal bloodstream at high levels where they may regulate maternal immune and vascular functions through receptor binding and modulation of cytokine and chemokine expression and activity. PSGs may have autocrine and paracrine functions in the placental bed, and PSGs can activate soluble and extracellular matrix bound TGF-β, with potentially diverse effects on multiple cell types. PSGs are also found at high levels in the maternal circulation, at least in human, where they may have endocrine functions. In a non-reproductive context, PSGs are expressed in the gastrointestinal tract and their deregulation may be associated with colorectal cancer and other diseases. Like many placental hormones, PSGs are encoded by multigene families and they have an unusual phylogenetic distribution, being found predominantly in species with hemochorial placentation, with the notable exception of the horse in which PSG-like proteins are expressed in the endometrial cups of the epitheliochorial placenta. The evolution and expansion of PSG gene families appears to be a highly active process, with significant changes in gene numbers and protein domain structures in different mammalian lineages, and reports of extensive copy number variation at the human locus. Against this apparent diversification, the available evidence indicates extensive conservation of PSG functions in multiple species. These observations are consistent with maternal-fetal conflict underpinning the evolution of PSGs.

Evolution of Placental Hormones: Implications for Animal Models

“…After initial duplication, the genes of many placental hormones have undergone further expansion to create multigene families. This is a contrast to adult hormones, which usually are encoded by a single gene ( 6 ). One explanation has been formulated in terms of parent-offspring conflict; a hypothesis based on conflicting priorities for allocation of maternal resources to the offspring.…”

“…These ideas were developed to explain the evolution of placental lactogens and their receptors ( 151 ). Parent-offspring conflict has also been suggested as a plausible explanation for the expansion of PSG genes in human (eleven genes), mouse (seventeen), and horse (seven genes) ( 6 ). It has also been alluded to with respect to the multigene family of PAGs ( 119 ).…”

“…Cross-species comparisons should be valuable in determining whether their primary role is to promote trophoblast invasion or to act as viral decoys. Although CEACAMs do act as viral decoys, there is no evidence that PSGS bind to microorganisms ( 6 ). The case is stronger for a role in immune tolerance of the invading trophoblast, especially in humans where PSGs, acting through TGFβ1, induce proliferation of regulatory T-cells in the uterus ( 46 , 130 ).…”

“…It has yet to be demonstrated conclusively that the primary function of PSGs is immunosuppression and promotion of trophoblast invasion. However, this is an active area of research ( 6 ).…”

“…PSGs do not occur in the guinea pig ( 6 ), but have not been sought in other rodents so it is not known if they evolved in the murid lineage or a deeper branch.…”