Nodal Expression in the Uterus of the Mouse Is Regulated by the Embryo and Correlates with Implantation1

Abstract

Nodal, a transforming growth factor beta (TGFB) superfamily member, plays a critical role during early embryonic development. Recently, components of the Nodal signaling pathway were characterized in the human uterus and implicated in the tissue remodeling events during menstruation. Furthermore, the Nodal inhibitor, Lefty, was identified in the mouse endometrium during pregnancy, and its overexpression led to implantation failure. Nonetheless, the precise function and mechanism of Nodal signaling during pregnancy remains unclear. In order to elucidate the potential roles Nodal plays in these processes, we have generated a detailed profile of maternal Nodal expression in the mouse uterus throughout pregnancy. NODAL, although undetectable during the nonpregnant estrus cycle, was localized throughout the glandular epithelium of the endometrium during the peri-implantation period. Interestingly, Nodal expression generated a banding pattern along the proximal-distal axis of the uterine horn on Day 4.5 that directly correlated with blastocyst implantation. Embryo transfer experiments indicate the embryo regulates Nodal expression in the uterus and directs its expression at the time of implantation, restricting NODAL to the sites between implantation crypts. During the later stages of pregnancy, Nodal exhibits a dynamic expression profile that suggests a role in regulating the endometrial response to decidualization and associated trophoblast invasion.

Activin/Nodal signalling before implantation: setting the stage for embryo patterning

“…Nodal expression persists in the epiblast and the PrE when these tissues segregate [23,71]. It is also detected in the endometrium of pregnant females at E3.5 [72], a potential source of Nodal of maternal origin to the blastocyst. Lefty1 expression is detected in a cluster of cells of the PrE when this layer forms [71,73].…”

NODAL signaling components regulate essential events in the establishment of pregnancy

“…Recently, Nodal expression in the uterus was documented throughout the estrus cycle and pregnancy using immunohistochemistry and a transgenic NodallacZ mouse strain that reports the sites of Nodal transcription (Park & Dufort 2011a). In this study, neither Nodal expression nor localized protein was detected at any point in the estrus cycle of nonpregnant mice.…”

“…In this study, neither Nodal expression nor localized protein was detected at any point in the estrus cycle of nonpregnant mice. However, Nodal was highly expressed in the uterine glandular epithelium throughout the pre-receptive phase (days 0.5-3.5) and positive immunoreactivity was detected along the luminal surface, suggesting NODAL secretion (Park & Dufort 2011a). Alternatively, Lefty1 mRNA was previously documented in uterine samples isolated from nonpregnant mice at all stages of the estrus cycle with moderately lower levels of expression during the estrus phase (stage of uterine expansion) (Tang et al 2005a).…”

“…Interestingly, whole-mount Nodal expression produced a banding pattern along the proximal-distal axis of the uterine horn that correlated exclusively with the inter-implantation nodes ( Fig. 2; Park & Dufort 2011a). This maternal Nodal expression is directed by the blastocyst as pseudopregnant females lost Nodal expression by day 4.5; however, the pattern was restored by wild-type embryo transfer experiments (Park & Dufort 2011a).…”

“…Together, these studies underscored the essential role of NODAL during mesendoderm induction and introduced an intriguing new member of the TGFB superfamily. Since its discovery, NODAL has been Nodal expression generates a banding pattern along the uterine horn at implantation; regulated by embryonic factors Park & Dufort (2011a) Uterine Nodal knockout females demonstrate subfertility due to reduced rates of establishing pregnancy Park et al (2012) LEFTY1/2 In vivo gene transfer of Lefty overexpression into the uterus leads to implantation failure Tang et al (2005b) FURIN, PACE4 Uterine-derived proprotein convertases are able to cleave and activate embryonic-derived NODAL at the time of implantation Mesnard & Constam (2010) …”