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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

An innate immune response and altered nuclear receptor activation defines the spinal cord transcriptome during alpha-tocopherol deficiency in Ttpa-null mice

Mice with deficiency in tocopherol (alpha) transfer protein gene develop peripheral tocopherol deficiency and sensory neurodegeneration. Ttpa-/- mice maintained on diets with deficient α-tocopherol (α-TOH) had proprioceptive deficits by six months of age, axonal degeneration and neuronal chromatolysis within the dorsal column of the spinal cord and its projections into the medulla. Transmission electron microscopy revealed degeneration of dorsal column axons. We addressed the potential pathomechanism of α-TOH deficient neurodegeneration by global transcriptome sequencing within the spinal cord and cerebellum. RNA-sequencing of the spinal cord in Ttpa-/- mice revealed upregulation of genes associated with the innate immune response, indicating a molecular signature of microglial activation as a result of tocopherol deficiency. For the first time, low level Ttpa expression was identified in the murine spinal cord. Further, the transcription factor liver X receptor (LXR) was strongly activated by α-TOH deficiency, triggering dysregulation of cholesterol biosynthesis. The aberrant activation of transcription factor LXR suppressed the normal induction of the transcription factor retinoic-related orphan receptor-α (RORA), which is required for neural homeostasis. Thus we find that α-TOH deficiency induces LXR, which may lead to a molecular signature of microglial activation and contribute to sensory neurodegeneration

A single-cell atlas of human and mouse white adipose tissue

none38noneMargo P. Emont, Christopher Jacobs, Adam L. Essene, Deepti Pant, Danielle Tenen, Georgia Colleluori, Angelica Di Vincenzo, Anja M. Jørgensen, Hesam Dashti, Adam Stefek, Elizabeth McGonagle, Sophie Strobel, Samantha Laber, Saaket Agrawal,Gregory P. Westcott, Amrita Kar, Molly L. Veregge, Anton Gulko, Harini Srinivasan, Zachary Kramer, Eleanna De Filippis, Erin Merkel, Jennifer Ducie, Christopher G. Boyd, William Gourash, Anita Courcoulas, Samuel J. Lin, Bernard T. Lee, Donald Morris, Adam Tobias, Amit V. Khera, Melina Claussnitzer, Tune H. Pers, Antonio Giordano, Orr Ashenberg, Aviv Regev, Linus T. Tsai & Evan D. RosenEmont, Margo P.; Jacobs, Christopher; Essene, Adam L.; Pant, Deepti; Tenen, Danielle; Colleluori, Georgia; DI VINCENZO, Angelica; Jørgensen, Anja M.; Dashti, Hesam; Stefek, Adam; Mcgonagle, Elizabeth; Strobel, Sophie; Laber, Samantha; Agrawal, Saaket; Westcott, Gregory P.; Kar, Amrita; Veregge, Molly L.; Gulko, Anton; Srinivasan, Harini; Kramer, Zachary; De Filippis, Eleanna; Merkel, Erin; Ducie, Jennifer; Boyd, Christopher G.; Gourash, William; Courcoulas, Anita; Lin, Samuel J.; Lee, Bernard T.; Morris, Donald; Tobias, Adam; Khera, Amit V.; Claussnitzer, Melina; Pers, Tune H.; Giordano, Antonio; Ashenberg, Orr; Regev, Aviv; Tsai &amp;, Linus T.; Rosen, Evan D