title: Left-Biased Spermatogenic Failure in 129/SvJ Dnd1Ter/+ Mice Correlates with Differences in Vascular Architecture, Oxygen Availability, and Metabolites.
abstract: Homozygosity for the Ter mutation in the RNA-binding protein Dead end 1 (Dnd1(Ter/Ter)) sensitizes germ cells to degeneration in all mouse strains. In 129/SvJ mice, approximately 10% of Dnd1(Ter/+) heterozygotes develop spermatogenic failure, and 95% of unilateral cases occur in the left testis. The first differences between right and left testes were detected at Postnatal Day 15 when many more spermatogonial stem cells (SSCs) were undergoing apoptosis in the left testis compared to the right. As we detected no significant left/right differences in the molecular pathway associated with body axis asymmetry or in the expression of signals known to promote proliferation, differentiation, and survival of germ cells, we investigated whether physiological differences might account for asymmetry of the degeneration phenotype. We show that left/right differences in vascular architecture are associated with a decrease in hemoglobin saturation and increased levels of HIF-1alpha in the left testis compared to the right. In Dnd1 heterozygotes, lower oxygen availability was associated with metabolic differences, including lower levels of ATP and NADH in the left testis. These experiments suggest a dependence on oxygen availability and metabolic substrates for SSC survival and suggest that Dnd1(Ter/+) SSCs may act as efficient sensors to detect subtle environmental changes that alter SSC fate.
authors.affiliation: Department of Cell Biology, Duke University, Durham, North Carolina Departmento Biomédico, Facultad de Ciencias de la Salud, Universidad de Antofagasta, Antofagasta, Chile.
authors.forename: Ximena M
authors.initials: XM
authors.lastname: Bustamante-Marin
authors.affiliation: Department of Cell Biology, Duke University, Durham, North Carolina Department of Anatomy, University of California, San Francisco, California.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Cook
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Departments of Pharmacology and Cancer Biology & Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Jessica
authors.initials: J
authors.lastname: Gooding
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Departments of Pharmacology and Cancer Biology & Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Christopher
authors.initials: C
authors.lastname: Newgard
authors.affiliation: Department of Cell Biology, Duke University, Durham, North Carolina blanche.capel@duke.edu.
authors.forename: Blanche
authors.initials: B
authors.lastname: Capel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001808:Blood Vessels / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D006454:Hemoglobins / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007248:Infertility, Male / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D010101:Oxygen Consumption; D012708:Sertoli Cells / Q000473:pathology; D013091:Spermatogenesis / Q000235:genetics*; D013093:Spermatogonia / Q000473:pathology; D013234:Stem Cells; D013737:Testis / Q000473:pathology
chemical_list: C500862:Dnd1 protein, mouse; D006454:Hemoglobins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins
keywords: Dnd1/DND1; germ cell; hypoxia; metabolism; spermatogenic failure; spermatogonial stem cells