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

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• 作者：Jiaxi Ding (1)
  DeChen Jiang (2)
  Michael Kurczy (3)
  Jennifer Nalepka (1)
  Brian Dudley (1)
  Erin I Merkel (4)
  Forbes D Porter (4)
  Andrew G Ewing (3) (5)
  Nicholas Winograd (3)
  James Burgess (2)
  Kathleen Molyneaux (1)
  
• 刊名：BMC Developmental Biology
• 出版年：2008
• 出版时间：December 2008
• 年：2008
• 卷：8
• 期：1
• 全文大小：4969KB
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• 作者单位：Jiaxi Ding (1)
  DeChen Jiang (2)
  Michael Kurczy (3)
  Jennifer Nalepka (1)
  Brian Dudley (1)
  Erin I Merkel (4)
  Forbes D Porter (4)
  Andrew G Ewing (3) (5)
  Nicholas Winograd (3)
  James Burgess (2)
  Kathleen Molyneaux (1)
  
  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, Kemiv盲gen 4, SE-41296, Gothenburg, Sweden
  

文摘

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.