Fatty acid amide hydrolase deficiency limits early pregnancy events
Haibin Wang, … , Benjamin F. Cravatt, Sudhansu K. Dey
Haibin Wang, … , Benjamin F. Cravatt, Sudhansu K. Dey
Published August 1, 2006
Citation Information: J Clin Invest. 2006;116(8):2122-2131. https://doi.org/10.1172/JCI28621.
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Research Article Reproductive biology

Fatty acid amide hydrolase deficiency limits early pregnancy events

Abstract

Synchronized preimplantation embryo development and passage through the oviduct into the uterus are prerequisites for implantation, dysregulation of which often leads to pregnancy failure in women. Cannabinoid/endocannabinoid signaling via cannabinoid receptor CB1 is known to influence early pregnancy. Here we provide evidence that a critical balance between anandamide synthesis by N-acylphosphatidylethanolamine–selective phospholipase D (NAPE-PLD) and its degradation by fatty acid amide hydrolase (FAAH) in mouse embryos and oviducts creates locally an appropriate “anandamide tone” for normal development of embryos and their oviductal transport. FAAH inactivation yielding higher anandamide or experimentally induced higher cannabinoid [(-)-Δ9-tetrahydrocannabinol] levels constrain preimplantation embryo development with aberrant expression of Cdx2, Nanog, and Oct3/4, genes known to direct lineage specification. Defective oviductal embryo transport arising from aberrant endocannabinoid signaling also led to deferred on-time implantation and poor pregnancy outcome. Intercrossing between wild-type and Faah–/– mice rescued developmental defects, not oviductal transport, implying that embryonic and maternal FAAH plays differential roles in these processes. The results suggest that FAAH is a key metabolic gatekeeper, regulating on-site anandamide tone to direct preimplantation events that determine the fate of pregnancy. This study uncovers what we believe to be a novel regulation of preimplantation processes, which could be clinically relevant for fertility regulation in women.

Authors

Haibin Wang, Huirong Xie, Yong Guo, Hao Zhang, Toshifumi Takahashi, Philip J. Kingsley, Lawrence J. Marnett, Sanjoy K. Das, Benjamin F. Cravatt, Sudhansu K. Dey

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Figure 5

Expression of Cdx2, Nanog, and Oct3/4 is aberrant in Faah-deficient morulae (A) and early (B) and late blastocysts (C).

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Expression of Cdx2, Nanog, and Oct3/4 is aberrant in ...
Confocal immunofluorescence shows Cdx2 expression (pink) in outer cells of morulae and in Tr cells of wild-type blastocysts. In contrast, Nanog (red) was clearly detected in a subset of inner cells of morulae and primarily in the ICM of blastocysts. While Oct3/4 (green) was detected in all cells of wild-type morulae (D3.5) and early blastocysts (D4), the expression was downregulated in Tr cells, with sustained expression in ICM cells in late expanded blastocysts (D4.25). In contrast, the expression patterns of Cdx2, Nanog, and Oct3/4 in Faah–/– embryos were aberrant. Unlike in wild-type embryos, Cdx2 expression was barely detected in Faah–/– morulae, but the expression in asynchronously developing mutant morulae and blastocysts on day 4 morning was comparable to that of wild-type embryos. While the expression of Nanog and Oct3/4 was observed in most cells in Faah–/– morulae, it was selectively downregulated in ICM cells, with sustained higher levels in Tr cells in mutant blastocysts in a stage-dependent manner (scale bar: 25 μm).