Research article

Inhibition of HMG CoA reductase reveals an unexpected role for cholesterol during PGC migration in the mouse

Jiaxi Ding¹ , DeChen Jiang² , Michael Kurczy³ , Jennifer Nalepka¹ , Brian Dudley¹ , Erin I Merkel⁴ , Forbes D Porter⁴ , Andrew G Ewing^3,5 , Nicholas Winograd³ , James Burgess² and Kathleen Molyneaux¹

¹  Department of Genetics Case Western Reserve University, Cleveland, OH, USA

²  Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA

³  Department of Chemistry, Penn State University, University Park, PA, USA

⁴  Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

⁵  Department of Chemistry, Gothenburg University, Kemivägen 4, SE-41296 Gothenburg, Sweden

author email corresponding author email

BMC Developmental Biology 2008, 8:120doi:10.1186/1471-213X-8-120

Published:	31 December 2008

Abstract

Background

Primordial germ cells (PGCs) are the embryonic precursors of the sperm and eggs. Environmental or genetic defects that alter PGC development can impair fertility or cause formation of germ cell tumors.

Results

We demonstrate a novel role for cholesterol during germ cell migration in mice. Cholesterol was measured in living tissue dissected from mouse embryos and was found to accumulate within the developing gonads as germ cells migrate to colonize these structures. Cholesterol synthesis was blocked in culture by inhibiting the activity of HMG CoA reductase (HMGCR) resulting in germ cell survival and migration defects. These defects were rescued by co-addition of isoprenoids and cholesterol, but neither compound alone was sufficient. In contrast, loss of the last or penultimate enzyme in cholesterol biosynthesis did not alter PGC numbers or position in vivo. However embryos that lack these enzymes do not exhibit cholesterol defects at the stage at which PGCs are migrating. This demonstrates that during gestation, the cholesterol required for PGC migration can be supplied maternally.

Conclusion

In the mouse, cholesterol is required for PGC survival and motility. It may act cell-autonomously by regulating clustering of growth factor receptors within PGCs or non cell-autonomously by controlling release of growth factors required for PGC guidance and survival.