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

Jiaxi Ding, Dechen Jiang, Michael Kurczy, Jennifer Nalepka, Brian Dudley, Erin I. Merkel, Forbes D. Porter, Andrew G. Ewing, Nicholas Winograd, James Burgess, Kathleen Molyneaux

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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.

Original languageEnglish (US)
Article number120
JournalBMC Developmental Biology
Volume8
DOIs
StatePublished - Dec 1 2008

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Hydroxymethylglutaryl CoA Reductases
Germ Cells
Cell Movement
Cholesterol
Cell Survival
Embryonic Structures
Growth Factor Receptors
Germ Cell and Embryonal Neoplasms
Terpenes
Gonads
Enzymes
Eggs
Fertility
Cluster Analysis
Spermatozoa
Intercellular Signaling Peptides and Proteins
Cell Count

ASJC Scopus subject areas

  • Developmental Biology

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Inhibition of HMG CoA reductase reveals an unexpected role for cholesterol during PGC migration in the mouse. / Ding, Jiaxi; Jiang, Dechen; Kurczy, Michael; Nalepka, Jennifer; Dudley, Brian; Merkel, Erin I.; Porter, Forbes D.; Ewing, Andrew G.; Winograd, Nicholas; Burgess, James; Molyneaux, Kathleen.

In: BMC Developmental Biology, Vol. 8, 120, 01.12.2008.

Research output: Contribution to journalArticle

Ding, J, Jiang, D, Kurczy, M, Nalepka, J, Dudley, B, Merkel, EI, Porter, FD, Ewing, AG, Winograd, N, Burgess, J & Molyneaux, K 2008, 'Inhibition of HMG CoA reductase reveals an unexpected role for cholesterol during PGC migration in the mouse', BMC Developmental Biology, vol. 8, 120. https://doi.org/10.1186/1471-213X-8-120
Ding, Jiaxi ; Jiang, Dechen ; Kurczy, Michael ; Nalepka, Jennifer ; Dudley, Brian ; Merkel, Erin I. ; Porter, Forbes D. ; Ewing, Andrew G. ; Winograd, Nicholas ; Burgess, James ; Molyneaux, Kathleen. / Inhibition of HMG CoA reductase reveals an unexpected role for cholesterol during PGC migration in the mouse. In: BMC Developmental Biology. 2008 ; Vol. 8.
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