Statins critical in formation of embryo

A single fertilized egg develops into a complete organism simply through repeated cycles of cell division. But, gaps remain in our understanding of how cells arrange themselves into each stage.

Researchers at Tokyo Medical and Dental University (TMDU) now know that the "primitive streak" in embryos – that groove that changes a single ball of cells with a single layer of ectoderm (outer layer) cells now involutes to make two interior layers — one of mesoderm (middle layer) and the other of endoderm (innermost layer) – but, cannot involute without statins.
Gastrulation preceedes all cell differentiation. Without this step, tissues don't organize into organs and systems of the body, and the egg dies.

Life Map • Embryonic Development

Researchers worked with mouse embryo stem cells to mimic human embryos. They used a wide range of drugs to stop embryo cell differentiation at each unique stage of development. But, statins block the mevalonate pathway, revealing it to be linked to formation of the primitive streak.

The work was published November 24, 2016 in Nature.

"When we applied statin drugs, which are extremely useful for lowering cholesterol levels, embryos stopped differentiating into cardiomyocytes [cardiac muscle cells] at a time when the primitive streak forms. Interference with the mevalonate pathway also reduced survival of the embryos."

Ruoxing Yu PhD, Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan and study coauthor

Similar experiments in zebrafish, another animal model used for biological studies, confirms that embryo development was stopped when the mevalonate pathway was blocked. The team then looked at specific effects of this blocked pathway and found a protein modification step called farnesylation.

Protein prenylation is a process by which water resistant molecules are added to a protein. Farnesylation is a type of prenylation process, but adds lipids or fats to the protein making protein to protein interactions and protein to membrane interactions smoother. Specifically, by attaching to the lamin-B protein. Farnesylation and prenylation increase the diversity of protein function by changing protein shapes.

"Discovery of involvement of the mevalonate pathway and lamin farnesylation processes in primitive streak formation increases our understanding of how embryos develop through gastrulation.

"This is important as statin drugs are widely used for lowering cholesterol, but forbidden in pregnancy. Our results shed light on how these drugs affect embryo development, helping us understand the guidelines regarding statin use in pregnant women."

Yoshimi Okamoto-Uchida PhD, Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku; Division of Medicinal Safety Science, National Institute of Health Sciences, Kamiyoga, Setagaya-ku, Tokyo, Japan, and lead author.

Abstract
The primitive streak in peri-implantation embryos forms the mesoderm and endoderm and controls cell differentiation. The metabolic cues regulating primitive streak formation remain largely unknown. Here we utilised a mouse embryonic stem (ES) cell differentiation system and a library of well-characterised drugs to identify these metabolic factors. We found that statins, which inhibit the mevalonate metabolic pathway, suppressed primitive streak formation in vitro and in vivo. Using metabolomics and pharmacologic approaches we identified the downstream signalling pathway of mevalonate and revealed that primitive streak formation requires protein farnesylation but not cholesterol synthesis. A tagging-via-substrate approach revealed that nuclear lamin B1 and small G proteins were farnesylated in embryoid bodies and important for primitive streak gene expression. In conclusion, protein farnesylation driven by the mevalonate pathway is a metabolic cue essential for primitive streak formation.

Scientific Reports 6, Article number: 37697 (2016)
doi:10.1038/srep37697
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TOP: Diagram of mouse embryonic development on indicated days.
BOTTOM: Mevalonate pathway in which farnesylation occurs in small G proteins and
the nuclear protein Lamin B1, triggering primitive streak formation.
Statins suppress farnesylation which inhibits induction of primitive streak genes.
Image Credit: Department of Developmental and Regenerative Biology,
Medical Research Institute,TMDU