Abstract
Abnormal uptake or metabolism of folate increases risk of human pregnancy complications, though the mechanism is unclear. Here, we explore how defective folate metabolism influences early development by analysing mice with the hypomorphic Mtrr gt mutation. MTRR is necessary for methyl group utilisation from folate metabolism, and the Mtrr gt allele disrupts this process. We show that the spectrum of phenotypes previously observed in Mtrr gt/gt conceptuses at embryonic day (E) 10.5 is apparent from E8.5 including developmental delay, congenital malformations, and placental phenotypes. Notably, we report misalignment of some Mtrr gt conceptuses within their implantation sites from E6.5. The degree of misorientation occurs across a continuum, with the most severe form visible upon gross dissection. Additionally, some Mtrr gt/gt conceptuses display twinning. Therefore, we implicate folate metabolism in blastocyst orientation and spacing at implantation. Skewed growth likely influences embryo development since developmental delay and heart malformations (but not defects in neural tube closure or trophoblast differentiation) associate with severe misalignment of Mtrr gt/gt conceptuses. Typically, the uterus is thought to guide conceptus orientation. To investigate a uterine effect of the Mtrr gt allele, we manipulate the maternal Mtrr genotype. Misaligned conceptuses were observed in litters of Mtrr +/+ , Mtrr +/gt , and Mtrr gt/gt mothers. While progesterone and/or BMP2 signalling might be disrupted, normal decidual morphology, patterning, and blood perfusion are evident at E6.5 regardless of conceptus orientation. These observations argue against a post-implantation uterine defect as a cause of conceptus misalignment. Since litters of Mtrr +/+ mothers display conceptus misalignment, a grandparental effect is explored. Multigenerational phenotype inheritance is characteristic of the Mtrr gt model, though the mechanism remains unclear. Genetic pedigree analysis reveals that severe conceptus skewing associates with the Mtrr genotype of either maternal grandparent. Moreover, the presence of conceptus skewing after embryo transfer into a control uterus indicates that misalignment is independent of the peri- and/or post-implantation uterus and instead is likely attributed to an embryonic mechanism that is epigenetically inherited. Overall, our data indicates that abnormal folate metabolism influences conceptus orientation over multiple generations with implications for subsequent development. This study casts light on the complex role of folate metabolism during development beyond a direct maternal effect.
Highlights
Maternal folate deficiency in humans is associated with increased risk of congenital malformations (MRC Vitamin Study Research Group, 1991) and pregnancy complications, such as placental abruption, hemorrhage, and preeclampsia (Wen et al, 2008)
We propose that defective folate metabolism disrupts blastocyst orientation and spacing over multiple generations, with implications for subsequent feto-placental development and a mechanism beyond a direct maternal effect
MTRR protein was widely expressed in wildtype embryonic and extraembryonic cell types including the yolk sac, amnion, allantois, and trophoblast progenitors at E8.5 (Figures 1A–C)
Summary
Maternal folate deficiency in humans is associated with increased risk of congenital malformations (MRC Vitamin Study Research Group, 1991) and pregnancy complications, such as placental abruption, hemorrhage, and preeclampsia (Wen et al, 2008). These complications potentially lead to increased risk of spontaneous abortion, miscarriage, or pre-term birth (Bukowski et al, 2009). For normal alignment to occur, mouse blastocysts attach to the antimesometrial uterine epithelium via the mural trophectoderm (opposes the inner cell mass (ICM)) by embryonic day (E) 4.5 and invade into the decidualizing endometrium (Smith, 1985; Cross et al, 1994). The extent to which deviation from normal conceptus alignment influences embryo and placenta development is not well understood
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