Reproduction in Domestic Animals

CL–Endometrium–Embryo Interactions 1072006a). IFNT is widely recognized as the maternalrecognition of pregnancy signal in ruminants (Robertset al. 2003) and establishes pregnancy by suppressingthe up-regulation of OXTR and ESR1 (Robinson et al.1999, 2001). Furthermore, recombinant IFNT caninhibit OXTR expression both in vivo (Spencer andBazer 1995, Spencer et al. 1998) and in vitro (Telgmannet al. 2003). However, what remains to be elucidated iswhether IFNT acts directly on the OXTR gene (Mannet al. 1999) or through suppression of the ESR1 gene(Spencer et al. 1996). The former hypothesis is supportedby the observations that the bovine OXTRpromoter region contains an interferon response element(IRE) and that interferon-regulatory factors(IRF)-1 and -2 bind to this site (Telgmann et al. 2003).Moreover, ESR1 was present in the luminal epitheliumof pregnant cows from day 12 to day 14 (Robinson et al.2001). Although Fleming et al. (2006) reported thatIRFs had no effect on the ovine OXTR promoter andmay represent a species difference.Interferon tau-stimulated genesInterferon tau also stimulates a plethora of endometrialgenes, which are likely to be important mediators forconceptus development and attachment to the endometrium.For example, IFNT suppresses the immunesystem by silencing genes, such as b2-microglobulinand major histocompatibility complex class 1 polypeptide-relatedsequence, thereby preventing the rejection ofthe conceptus allograft. IFNT also stimulates genesinvolved in cell proliferation (e.g. Wnt7a), uterinereceptivity and conceptus attachment (e.g. Galectin 15,mucins, cathepsin L). For extensive reviews on theeffects of IFNT on endometrial functions, see Demmerset al. (2001) and Spencer et al. (2007, 2008).Endometrial–embryonic interactionsThe endometrium and embryo secrete a number ofcytokines and growth factors (Martal et al. 1997). Theseinclude the IGF system, fibroblast growth factor (FGF)-1 and -2, transforming growth factor (TGF) a and b andepidermal growth factor (EGF). The precise role ofthese factors is currently unclear, but they are likely toplay an important role in the regulation of pre-attachmentblastocyst development, uterine receptivity andstimulation of IFNT secretion (Roberts et al. 2003;Imakawa et al. 2004). There is a strong link betweenmetabolic status and reproductive function (Watheset al. 2003). Thus, the IGF system is particularlyinteresting as IGF1 is an important intermediary ofmetabolic status. For example, systemic lower IGF1concentrations at two weeks post-partum were associatedwith a longer time to conception as a consequenceof impaired ovarian and uterine function (Wathes et al.2003, 2007; Taylor et al. 2004). IGF1 and its bindingproteins (IGFBPs) are expressed in the endometriumand are regulated during the oestrous cycle. IGF1mRNA is present in the endometrium through theoestrous cycle (Geisert et al. 1991; Robinson et al. 2000)with up-regulation during oestrus and during the midlutealphase (Robinson et al. 2000). Moreover, IGF1(Kirby et al. 1996; Robinson et al. 2000) and IGF2(Geisert et al. 1991; Bilby et al. 2006) mRNA expressionis increased during early pregnancy. This raises thepossibility that either the embryo up-regulates thesegenes or that embryo development was enhanced inanimals with increased levels of IGF1 and ⁄ or IGF2.Moreover, IGF1 in concert with IGF2 can stimulate theproduction of IFNT (Ko et al. 1991). These observationscombined with the fact that systemic IGF1concentrations are attenuated in cattle with poor fertility(Wathes et al. 2003), indicate that IGFs are likely toplay a key role in regulating endometrial function andsubsequent embryonic development. The endometrial–embryonic interactions through the IGF system aresummarized in Fig. 1.The bioavailability of IGFs is influenced by theIGFBPs, which are generally considered to sequesterIGFs, but can also promote IGF action. Interestingly,IGFBP levels are differentially regulated during pregnancywith IGFBP2 mRNA and IGFBP3 mRNA beingdown-regulated (Geisert et al. 1991; Robinson et al.2000), while IGFBP1 mRNA was up-regulated in thepresence of an embryo (Robinson et al. 2000). Theexpression pattern of IGFBP1 mRNA was particularlyinteresting as it was expressed in the luminal epitheliumIGFBP1IGFBP2IGF2MyometriumHistotrophIGF1RIGF1R (proliferation)IGF1IGF2(IGF1)IGFBP1 IGFBP2IGFBP3 IGFBP5IGF1R(proliferation)IGF1Systemic IGF1IGFBP5IGFBP3E 2ConceptusIFNTIGFBP1PGRCaruncleBlood vesselFig. 1. A working hypothesis of the inter-relationships between thecomponents of the insulin-like growth factor (IGF) system duringearly pregnancy in the cow. IGF-1 (endometrial-derived) and IGF2(embryonic-derived) stimulate conceptus growth and secretion ofinterferon tau (IFNT). These effects are likely to be modulated byIGF-binding protein (IGFBP) 1 (from luminal epithelium; dark-greybox) and IGFBP2 (from sub-epithelial stroma, light-grey box). Based onits expression patterns, IGFBP1 expression is stimulated by IFNT butsuppressed by progesterone. IGF1 acting through IGF type 1 receptors(IGF1R) also stimulates the secretion of required histotroph from theendometrial glands. IGF2 action, modulated by IGFBP3 and IGFBP5 islikely to stimulate caruncular development. IGFBP3 may also play arole in regulating the availability of systemic IGF1, while IGFBP5was localized to the myometrium. The dotted line indicates proposedregulatory mechanisms; the solid dot represents up-regulation_Ó 2008 The Authors. Journal compilation Ó 2008 Blackwell Verlag