Jiaxi Ding1 , DeChen Jiang2 , Michael Kurczy3 , Jennifer Nalepka1 , Brian Dudley1 , Erin I Merkel4 , Forbes D Porter4 , Andrew G Ewing3,5 , Nicholas Winograd3 , James Burgess2 and Kathleen Molyneaux1
1Department of Genetics Case Western Reserve University, Cleveland, OH, USA
2Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA
3Department of Chemistry, Penn State University, University Park, PA, USA
on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver
National Institute of Child Health and Human Development, National
Institutes of Health, Bethesda, MD, USA
5Department of Chemistry, Gothenburg University, Kemivägen 4, SE-41296 Gothenburg, Sweden
BMC Developmental Biology 2008,
8:120 [Open Access]
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.
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.
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.