FERTILITY: Molecular defect for one form of male factor infertility uncovered

The sperm that successfully fertilizes an egg triggers a series of events, known collectively as egg activation, that are considered the first step in the initiation of embryo development. Detection of egg activation is used by clinics to determine whether an in vitro fertilization procedure (a process whereby egg cells are fertilized by sperm in a test tube) has been successful. The sperm of some patients who repeatedly fail the in vitro fertilization technique ICSI, which is used to treat male factor infertility, fail to induce egg activation, and the patients are therefore sterile. Rafael Fissore and colleagues, at the University of Massachusetts, Amherst, have now uncovered one molecular defect underlying such sterility: the sperm lack detectable levels of the protein PLC, zeta-1.

TITLE: Human sperm devoid of PLC, zeta 1 fail to induce Ca2+ release and are unable to initiate the first step of embryo development

Rafael A. Fissore
University of Massachusetts, Amherst, Massachusetts, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36942

ONCOLOGY: Take it down a Notch(1): new role for Notch1 in facilitating melanoma development

One of the most aggressive forms of cancer is a type of skin cancer known as melanoma. Melanomas are the least common type of skin cancer but account for the majority of deaths from skin cancer, in part because they are resistant to most conventional therapies (chemotherapies and radiation treatment). Marianne Broome-Powell and colleagues, at Stanford University, have previously found that a shortage of oxygen (hypoxia) in the skin contributes to the development of melanomas in conjunction with activation of a signaling protein known as Akt. Now, however, using human melanoma samples and cells lines as well as a xenograft model of melanoma development, they have identified another signaling protein that is required for Akt and hypoxia to cause melanoma development, Notch1. These data suggest that targeting the Notch signaling pathway might provide a new therapeutic approach to treating melanoma.

TITLE: Notch1 is an effector of Akt and hypoxia in melanoma development

Marianne Broome Powell
Stanford University, Stanford, California, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36157

INFLAMMATION: Platelets go with their gut feeling, helping promote intestinal inflammation

Sean Colgan and colleagues, at the University of Colorado Denver School of Medicine, Aurora, have provided new insight into the function of nonimmune blood cells known as platelets in the inflamed intestine, and suggest that platelets might help promote bacterial clearance under inflammatory conditions.

In the study, platelets were found to be able to efficiently cross a monolayer of epithelial cells (the cells that line the intestine) only when immune cells known as PMNs were also present and able to cross. Similar comigration of platelets and PMNs was observed in intestinal tissue from human patients with inflammatory bowel disease. Further studies, in vitro and in a mouse model of intestinal inflammation, indicated that platelets that crossed the epithelial cells triggered epithelial cell secretion of chloride ions, and therefore water, into the intestine. The mechanism underlying this effect was shown to involve platelet release of large amounts of ATP, which was then broken down to adenosine (the molecule responsible for triggering epithelial cell secretion of chloride ions) by proteins such as CD73 and ecto-NTPDases on the surface of epithelial cells.

TITLE: PMNs facilitate translocation of platelets across human and mouse epithelium and together alter fluid homeostasis via epithelial cell-expressed ecto-NTPDases

Sean P. Colgan
University of Colorado Denver School of Medicine, Aurora, Colorado, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35874

METABOLIC DISEASE: The protein ABCG1 helps keep cells lining blood vessels healthy

One of the main causes of heart attack and stroke is a disease known as atherosclerosis (sometimes simply referred to as hardening of the arteries), which affects the major arterial blood vessels. One predictor of an individual's risk of developing atherosclerosis is the level of the molecule HDL in the blood, high levels have a protective effect. New data, generated in mice, by Naoki Terasaka and colleagues, at Columbia University College of Physicians and Surgeons, New York, have provided new insight into the atheroprotective effects of HDL: they ensure that the cells lining the major arterial blood vessels (endothelial cells) are able to continue functioning as normal.

In the study, arteries from mice lacking the protein ABCG1 and from mice lacking both ABCA1 and ABCG1 showed decreased endothelial cell-dependent functions when they were analyzed after the mice had been fed a diet that induces atherosclerosis. Further analysis revealed that endothelial cells from these mice had specific molecular defects, including an accumulation of cholesterol and cholesterol-related molecules. A similar role for ABCG1 in preventing the accumulation of cholesterol within cells was observed when human aortic endothelial cells were analyzed. Furthermore, treatment of these human cells with HDL prevented the accumulation of cholesterol in an ABCG1-dependent manner. As ABCG1 is known to promote the efflux of cholesterol from other cell types in a process that involves HDL, the authors suggest that ABCG1 and HDL maintain the function of endothelial cells in mice fed a diet that induces atherosclerosis, in part by promoting the efflux of cholesterol and other related fats.

TITLE: ABCG1 and HDL protect against endothelial dysfunction in mice fed a high-cholesterol diet

Naoki Terasaka
Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35470

VASCULAR BIOLOGY: O-glycan control of lymphatic vessel development

Molecules known as O-glycans have an essential role in embryonic vascular development, but the cell type in which they need to be expressed has not been determined. Now, however, Lijun Xia and colleagues, at Oklahoma Medical Research Foundation, Oklahoma City, have found that O-glycans in endothelial cells (the cells that line blood and lymphatic vessels) are required for lymphatic vessel development in mice.

The authors generated mice lacking T-synthase, a protein critical for making O-glycans, in endothelial cells and blood cells (EHC T-syn-/- mice). Most EHC T-syn-/- mice died in utero or soon after birth, and death was associated with disorganized and blood-filled lymphatic vessels caused by abnormal connections between blood and lymphatic vessels. Mechanistic insight was provided by the observation that levels of the molecule podoplanin were decreased in EHC T-syn-/- ECs and that mice lacking podoplanin exhibited similar lymphatic vessel defects to EHC T-syn-/- mice. Thus, the separation of blood and lymphatic vessels during embryonic development seems to be controlled by endothelial cell O-glycans, in part through their ability to regulate podoplanin expression. Further, as postnatal deletion of the gene encoding T-synthase also caused abnormal connections between blood and lymphatic vessels, the same mechanism is likely to be operational in adult mice.

TITLE: Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice

Lijun Xia
Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36077


Source: Karen Honey
Journal of Clinical Investigation