Review

Abstract

Uric acid is the metabolic end product of purine metabolism in humans. It has antioxidant properties that may be protective but can also be pro-oxidant, depending on its chemical microenvironment. Hyperuricemia predisposes to disease through the formation of urate crystals that cause gout, but hyperuricemia, independent of crystal formation, has also been linked with hypertension, atherosclerosis, insulin resistance, and diabetes. We discuss here the biology of urate metabolism and its role in disease. We also cover the genetics of urate transport, including URAT1, and recent studies identifying SLC2A9, which encodes the glucose transporter family isoform Glut9, as a major determinant of plasma uric acid levels and of gout development.

Authors

Alexander So, Bernard Thorens

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Abstract

The CNS is an immune-privileged environment, yet the local control of multiple pathogens is dependent on the ability of immune cells to access and operate within this site. However, inflammation of the distinct anatomical sites (i.e., meninges, cerebrospinal fluid, and parenchyma) associated with the CNS can also be deleterious. Therefore, control of lymphocyte entry and migration within the brain is vital to regulate protective and pathological responses. In this review, several recent advances are highlighted that provide new insights into the processes that regulate leukocyte access to, and movement within, the brain.

Authors

Emma H. Wilson, Wolfgang Weninger, Christopher A. Hunter

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Abstract

The linkage of Kaposi sarcoma (KS) to infection by a novel human herpesvirus (Kaposi sarcoma–associated herpesvirus [KSHV]) is one of the great successes of contemporary biomedical research and was achieved by using advanced genomic technologies in a manner informed by a nuanced understanding of epidemiology and clinical investigation. Ongoing efforts to understand the molecular mechanisms by which KSHV infection predisposes to KS continue to be powerfully influenced by insights emanating from the clinic. Here, recent developments in KS pathogenesis are reviewed, with particular emphasis on clinical, pathologic, and molecular observations that highlight the many differences between this process and tumorigenesis by other oncogenic viruses.

Authors

Don Ganem

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Abstract

Spermatogenesis in adult mammals is highly organized, with the goal being continual sperm production. Vertebrate testes are arranged into recurring cellular associations that vary with time and distance along the tubule. These changes over time and distance are designated the cycle of the seminiferous epithelium and the spermatogenic wave, respectively. In this Review, we briefly outline the roles that follicle-stimulating hormone (FSH) and testosterone play in regulating spermatogenesis and describe our current understanding of how vitamin A regulates germ cell differentiation and how it may lead to the generation of both the cycle of the seminiferous epithelium and the spermatogenic wave.

Authors

Cathryn A. Hogarth, Michael D. Griswold

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Abstract

Human reproduction is relatively inefficient. Nearly 30% of pregnancies result in spontaneous losses, which are both a clinical problem and a psychological stress to the families involved. Furthermore, although the human population is growing rapidly and is predicted to reach 9 billion by 2050, 15% of couples worldwide are childless because of infertility. Many underlying causes of infertility have been overcome by assisted reproductive technologies such as in vitro fertilization, yet pregnancy success rates using such approaches remain disappointingly low. Since mechanistic approaches to study human reproductive processes are ethically restricted, future advances in fertility treatment and the development of new contraceptives rely predominantly on the study of the factors influencing reproduction in model systems. The articles in this Reproductive Biology Review series present updates on the current understanding of various reproductive processes in model systems and raise questions that need to be addressed if we are to improve human reproductive health.

Authors

Sudhansu K. Dey

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Abstract

Mammalian preimplantation development, which is the period extending from fertilization to implantation, results in the formation of a blastocyst with three distinct cell lineages. Only one of these lineages, the epiblast, contributes to the embryo itself, while the other two lineages, the trophectoderm and the primitive endoderm, become extra-embryonic tissues. Significant gains have been made in our understanding of the major events of mouse preimplantation development, and recent discoveries have shed new light on the establishment of the three blastocyst lineages. What is less clear, however, is how closely human preimplantation development mimics that in the mouse. A greater understanding of the similarities and differences between mouse and human preimplantation development has implications for improving assisted reproductive technologies and for deriving human embryonic stem cells.

Authors

Katie Cockburn, Janet Rossant

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Abstract

Much of our knowledge of human uterine physiology and pathology has been extrapolated from the study of diverse animal models, as there is no ideal system for studying human uterine biology in vitro. Although it remains debatable whether mouse models are the most suitable system for investigating human uterine function(s), gene-manipulated mice are considered by many the most useful tool for mechanistic analysis, and numerous studies have identified many similarities in female reproduction between the two species. This Review brings together information from studies using animal models, in particular mouse models, that shed light on normal and pathologic aspects of uterine biology and pregnancy complications.

Authors

Hyunjung Jade Lim, Haibin Wang

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Abstract

The placenta provides critical transport functions between the maternal and fetal circulations during intrauterine development. Formation of this interface relies on coordinated interactions among transcriptional, epigenetic, and environmental factors. Here we describe these mechanisms in the context of the differentiation of placental cells (trophoblasts) and synthesize current knowledge about how they interact to generate a functional placenta. Developing an understanding of these pathways contributes to an improvement of our models for studying trophoblast biology and sheds light on the etiology of pregnancy complications and the in utero programming of adult diseases.

Authors

Emin Maltepe, Anna I. Bakardjiev, Susan J. Fisher

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Abstract

The classical view of ovarian follicle development is that it is regulated by the hypothalamic-pituitary-ovarian axis, in which gonadotropin-releasing hormone (GnRH) controls the release of the gonadotropic hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and that ovarian steroids exert both negative and positive regulatory effects on GnRH secretion. More recent studies in mice and humans indicate that many other intra-ovarian signaling cascades affect follicular development and gonadotropin action in a stage- and context-specific manner. As we discuss here, mutant mouse models and clinical evidence indicate that some of the most powerful intra-ovarian regulators of follicular development include the TGF-β/SMAD, WNT/FZD/β-catenin, and RAS/ERK1/2 signaling pathways and the FOXO/FOXL2 transcription factors.

Authors

JoAnne S. Richards, Stephanie A. Pangas

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Abstract

Mammalian fertilization comprises sperm migration through the female reproductive tract, biochemical and morphological changes to sperm, and sperm-egg interaction in the oviduct. Recent gene knockout approaches in mice have revealed that many factors previously considered important for fertilization are largely dispensable, or if they are essential, they have an unexpected function. These results indicate that what has been observed in in vitro fertilization (IVF) differs significantly from what occurs during “physiological” fertilization. This Review focuses on the advantages of studying fertilization using gene-manipulated animals and highlights an emerging molecular mechanism of mammalian fertilization.

Authors

Masahito Ikawa, Naokazu Inoue, Adam M. Benham, Masaru Okabe

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