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The mevalonate pathway regulates primitive streak formation via protein farnesylation

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Involvement of the mevalonate pathway in primitive streak formation in mouse embryos.Top: Schematic diagram of mouse embryonic development on the indicated days. Bottom: The mevalonate pathway produces farnesyl diphosphate for cholesterol synthesis, protein geranylgeranylation and protein farnesylation. The farnesylation of various proteins, including small G proteins and the nuclear protein Lamin B1, triggers primitive streak formation. Statins inhibit the induction of primitive streak genes by suppressing protein farnesylation. Consistent with our observations, Hmgcr KO mice and FTase KO mice are embryonic lethal at E8.5 and E7.5, respectively2122.
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f5: Involvement of the mevalonate pathway in primitive streak formation in mouse embryos.Top: Schematic diagram of mouse embryonic development on the indicated days. Bottom: The mevalonate pathway produces farnesyl diphosphate for cholesterol synthesis, protein geranylgeranylation and protein farnesylation. The farnesylation of various proteins, including small G proteins and the nuclear protein Lamin B1, triggers primitive streak formation. Statins inhibit the induction of primitive streak genes by suppressing protein farnesylation. Consistent with our observations, Hmgcr KO mice and FTase KO mice are embryonic lethal at E8.5 and E7.5, respectively2122.

Mentions: Importantly, the U.S. Food and Drug Administration has classified ATV to pregnancy category X, meaning that the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. However, our data show that the mevalonate (HMGCR) pathway is essential for the formation of the primitive streak in cultured EBs and in mice (Fig. 5, Supplementary Figure 3), and suggest an embryotoxic effect of statin on mammalian embryos, which should help better inform these guidelines.


The mevalonate pathway regulates primitive streak formation via protein farnesylation
Involvement of the mevalonate pathway in primitive streak formation in mouse embryos.Top: Schematic diagram of mouse embryonic development on the indicated days. Bottom: The mevalonate pathway produces farnesyl diphosphate for cholesterol synthesis, protein geranylgeranylation and protein farnesylation. The farnesylation of various proteins, including small G proteins and the nuclear protein Lamin B1, triggers primitive streak formation. Statins inhibit the induction of primitive streak genes by suppressing protein farnesylation. Consistent with our observations, Hmgcr KO mice and FTase KO mice are embryonic lethal at E8.5 and E7.5, respectively2122.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121603&req=5

f5: Involvement of the mevalonate pathway in primitive streak formation in mouse embryos.Top: Schematic diagram of mouse embryonic development on the indicated days. Bottom: The mevalonate pathway produces farnesyl diphosphate for cholesterol synthesis, protein geranylgeranylation and protein farnesylation. The farnesylation of various proteins, including small G proteins and the nuclear protein Lamin B1, triggers primitive streak formation. Statins inhibit the induction of primitive streak genes by suppressing protein farnesylation. Consistent with our observations, Hmgcr KO mice and FTase KO mice are embryonic lethal at E8.5 and E7.5, respectively2122.
Mentions: Importantly, the U.S. Food and Drug Administration has classified ATV to pregnancy category X, meaning that the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. However, our data show that the mevalonate (HMGCR) pathway is essential for the formation of the primitive streak in cultured EBs and in mice (Fig. 5, Supplementary Figure 3), and suggest an embryotoxic effect of statin on mammalian embryos, which should help better inform these guidelines.

View Article: PubMed Central - PubMed

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.

No MeSH data available.