JCI table of contents September 15, 2004


Venn Diagram Tactics to Vet Complex Disease

A whole range of human muscular and neuromuscular diseases, are caused by mutations in the mitochondrial respiratory chain/oxidative phosphorylation system. The problem is that there are about 120 genes involved in this system, some that are found in the mitochondria, and thus inherited through the mother, and some that are found in the nucleus and are inherited from both the mother and the father. Between the number of genes involved and the variable inheritance patterns, identifying all the mutations that could cause disease is a daunting task. Now David Thorburn and colleagues, from Murdoch Childrens Research Institute, have developed a methodology that takes a "Venn Diagram" approach to efficiently pinpoint mutations in this system. They utilize this method to identify a new cause for a lethal neonatal disease. The strategy makes use of cell-fusion experiments where cells from different patients are fused and the authors ask whether the fused cells are no longer defective -- this means the cells can complement one another. If the fused cells complement each other, this means that the original cells had mutations in different genes. The authors then carry out a second round of fusions, but in these cells, they have had the mitochondrial DNA removed. Here, if the fused cells are no longer defective, the mutation is in the patient's nuclear DNA. If the fusions remain defective, the causal mutation is likely to be in the mitochondrial DNA. This technique is a very rapid and powerful means to categorize the mutation type of cells from different patients. The authors effectively demonstrated the strength of this technique using cells from 10 different patients, and showed that 7 contained nuclear mutations and 1 contained a mitochondrial mutation. The authors then focused on two patients whose cells did not complement one another, meaning the same gene was mutated. From there they used a battery of mapping, microarray and bioinformatics analyses and identified mutations for both patients in the NDUFS6 gene; a gene not previously shown to be involved in this type of disease. This work shows how combining a series of analyses, including genetic, biochemical, microarray, and bioinformatics techniques provide a rapid and effective means to pinpoint mutations in diseases that have complex genetic backgrounds.

An accompanying commentary by Eric Schon provides an overview of the complexity of the mitochondrial respiratory chain/oxidative phosphorylation system and a detailed discussion of the techniques used in this paper.

TITLE: NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency

David R. Thorburn
Murdoch Childrens Research Institute, Royal Children's Hospital, Flemington Rd, Parkville, Victoria 3052, Australia
Phone: 613-8341-6235; Fax: 613-8341-6212; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/20683.pdf

ACCOMPANYING COMMENTARY: Complements of the house

Eric A. Schon
Columbia University, 630 West 168th St. New York, NY 10032, USA
Phone: 212-305-1665; Fax: 212-305-3986; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/22942.pdf

Picking Prostanoids to Provide Protection

Atherosclerosis is an inflammation in the lining of the arteries. Biological chemicals in the body called pros-tanoids, which are made from the breakdown of arachidonic acid by the action of an enzyme called COX have been implicated in the development of atherosclerosis. The role of prostanoids in inflammation is well known, based on studies of aspirin-like non-steroidal anti-inflammatory drugs, which act to inhibit the action of COX. Two prostenoids called PG I2/prostacyclin (PGI2) and thromboxane A2 (TXA2), are ele-vated in individuals with atheroscle-rosis, but their roles in the initiation and development of atherosclerosis remain ill-defined. To investigate the role of each of these prostanoids in atherosclerosis, Shuh Narumiya and colleagues, of Kyoto University Faculty of Medicine, have bred an ath-erosclerotic mouse model (apoE–/–) with mice that were deficient in either the PGI receptor (IP) or the TXA receptor (TP). These mice allowed the authors to examine the effect of loss of PGI or TXA action on atherosclerosis development. Relative to apoE–/– mice, the apoE–/–IP–/– mice had accelerated initiation and development of athero-sclerosis, while the apoE–/–TP–/– mice had delayed development. apoE–/–IP–/– mice also demonstrated other mark-ers of more severe disease, compared with apoE–/– mice. apoE–/–TP–/– mice presented with fewer markers of dis-ease. These data indicate that PGI2 protects against and TXA2 promotes atherosclerosis development. The use of TP antagonists and molecules with PG-like activity may therefore aid in atherosclerosis prevention. Furthermore these data fit well with previous work that indicated that low doses of aspirin, which inhibits TXA2 more than PGI2, has been used as anti-platelet therapy for the prevention of myocardial infarction and recurrence of strokes.

TITLE: Roles of thromboxane A2 and prostacyclin in the development of atherosclerosis in apoE-deficient mice

Shuh Narumiya
Kyoto University Faculty of Medicine, Yoshida, Sakyoku, Kyoto 606-8501, Japan
Phone: 81-75-753-4392; Fax: 81-75-753-4693; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/21446.pdf

New Veins of Thought for Retinal Degeneration

Retinal degeneration is inherited by as many as 1 in 3,500 individuals. The underlying genetic basis and the clinical symptoms vary, but generally the result is profound vision loss, most often caused by the death of retinal neuronal through a form a cellular suicide called apoptosis. In many cases the vasculature in the retina also becomes atrophied. It remains uncertain, however, if the vasculature atrophy is secondary to the degeneration of the retina. To investigate the importance of vascular atrophy in retinal degeneration, Martin Friedlander and colleagues, from the Scripps Research Institute, transplanted mouse or human adult bone-marrow–derived stem cells in the retinal nuclear layers of two different mouse models for retinal degeneration. The researchers found that, in both mouse models of retinal degeneration, whenever the transplanted stem cells stabilized and rescued the retinal blood vessels that would ordinarily completely degenerate, they also saw a striking rescue effect on the retinal neuronal cells. Of interest, while the mouse retina is primarily made up of rod cells, the cells that see black and white, the rescued cells after treatment were almost always cone cells, the cells that detect color. The researchers further showed, using microarray analysis, that in the treated retinas, several genes that showed increased expression were genes involved in blocking cell death. Taken together, the data from this study indicates that regardless of the underlying genetic defect, the relationship between retinal vasculature and its associated retinal neuronal tissue should be considered together when developing potential treatments for delaying or preventing retinal degeneration.

An accompanying commentary by Lois Smith, of the Children's Hospital in Boston, discusses the effect of stem cells transplantation on the retinal vasculature and the protection the cones. The commentary also discusses the therapeutic potential using the strategy presented.

TITLE: Rescue of retinal degeneration by intravitreally injected adult bone marrow–derived lineage-negative hematopoietic stem cells

Martin Friedlander
The Scripps Research Institute, 10550 North Torrey Pines Rd, La Jolla, CA 92037, USA
Phone: 858-784-9138; Fax: 858-784-9135; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/21686.pdf

ACCOMPANYING COMMENTARY: Bone marrow–derived stem cells preserve cone vision in retinitis pigmentosa

Lois E.H. Smith
Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA
Phone: 617-919-2529; Fax: 617-730-0392; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/22930.pdf

No Compensation Without PDX-1

Extra growth of pancreatic b cells can reduce the effects of insulin resistance. Loss of this compensatory increased growth, however, often results in the development of diabetes. Rohit Kulkarni and colleagues, or the Joslin Diabetes Center, examined this islet-growth response in two dif-ferent insulin-resistance mouse models. The researchers found that when they brought pancreatic homeodomain protein (PDX-1) haploinsufficiency into the background of either insulin receptor/insulin receptor substrate–1 double-heterozygous mice or liver-specific insulin receptor knockouts, b cell growth was severely limited. Further analyses provided evidence that the hyperplasia loss was due to a reduction in b cell growth and to an extensive increase in programmed cell death. While PDX-1 is known to be important for pancreatic progenitor cell growth, these studies indicate that it also has a vital role in regulating adult b cell pro-liferation and is a key component of the mechanisms underlying compensatory b cell hyperplasia in response to insulin resistance.

TITLE: PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance

Rohit N. Kulkarni
Joslin Diabetes Center One Joslin Pl, Boston, MA 02215, USA
Phone: 617-713-3460; Fax: 617-713-3476; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/21845.pdf

Become One: Beat as One

Skeletal myoblast transplantation into injured hearts can limit adverse remodeling. Understanding of donor-host interaction at a cellular level, however, is currently limited. To gain insight into this system, Loren J. Field and colleagues, at the Indiana University School of Medicine, transplanted enhanced GFP–expressing (EGFP-expressing) myoblasts into nontransgenic mouse recipient hearts and examined intracellular calcium transients using two-photon molecular excitation laser scanning microscopy (pages 775–783). Synchronous intracellular calcium transients occurred primarily only in host cardiomyocytes, but did also occur in a small fraction of donor-derived myocytes at the graft-host border. EGFP-marked donor myoblasts were transplanted into hearts of transgenic mice expressing a cardiomyocyte-restricted b-gal reporter gene, where histology demonstrated a small portion of myocytes expressed both donor- and host-derived transgenes, indicating fusion of these cells. These double-expressing cells had incidence and location similar to that of the functionally coupled EGFP-positive myocytes. This study indicates that while most engrafted donor-derived myocytes remain functionally separate from host myocardium cells, a small subset of skeletal myoblasts at the myocardial/skeletal muscle interface can become functionally coupled with host cardiomyoblasts, likely through fusion events between donor and host cells.

TITLE: Spontaneous and evoked intracellular calcium transients in donor-derived myocytes following intracardiac myoblast transplantation

Loren J. Field
Indiana University School of Medicine, 1044 West Walnut St, Indianapolis, IN 46202, USA
Phone: 317-274-5085; Fax: 317-274-8679; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/21589.pdf

Pathways to Immunity

The presence of bacterial components triggers Toll-like receptors (TLRs) to activate macrophages and DCs through various signal transduction pathways. In response to LPS, a TLR turns on the serine/threonine kinase Cot/Tpl2, which then activates ERK1/2 in macrophages. It remains unknown whether Cot/Tpl2 is involved in responses to other bacterial components or in the activa-tion of other immune cell types. Tetsuya Matsuguchi and colleagues examine the importance of Cot/Tpl2 in response to LPS, synthetic lipopeptide, and bacterial DNA (CpG-DNA) (pages 857–866). Using RAW 264.7 cells, the authors showed that all 3 ligands activated Cot/Tpl2. In peritoneal macrophages from Cot/Tpl2–/– mice, however, only CpG-DNA could activate ERK, thus it could function through a Cot/Tpl2-independent pathway. Both peritoneal macrophages and immature DCs from the bone marrow of Cot/Tpl2–/– mice showed increased IL-12 expression in response to CpG-DNA. Northern blot analysis and gel shift assays demonstrated that enhanced IL-12 levels occurred at least partially through loss of transcriptional repression. In vivo, OVA immunization and Leishmania major infection in Cot/Tpl2-deficient mice showed Th1-skewed antigen-specific immune responses. This study indicates that Cot/Tpl2 may be a significant regulator of the Th1/Th2 balance through negative regulation of IL-12 and may therefore be a useful target molecule for improving CpG-DNA–guided vaccination.

TITLE: A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA–induced IL-12 production and Th cell differentiation

Tetsuya Matsuguchi
Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
Phone: 81-99-275-6130; Fax: 81-99-275-6138; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/20014.pdf


Prostanoid Promotes Renal Pressure

TITLE: Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I2 receptor IP

Fumitaka Ushikubi
Asahikawa Medical College, Midorigaoka Higashi 2-1-1-1, Asahikawa 078-8510, Japan
Phone: 81-166-68-2362; Fax: 81-166-68-2369; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/21382.pdf

ACCOMPANYING COMMENTARY: Prostanoids and blood pressure: which way is up?

Thomas M. Coffman
Durham Veteran Affairs Medical Center, 508 Fulton St, Durham, NC 27705, USA
Phone: 919-286-6947; Fax: 919-286-6879; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/22929.pdf

Atherosclerosis: The NOS Have It

TITLE: T cell–mediated vascular dysfunction of human allografts results from IFN-g dysregulation of NO synthase

AUTHOR CONTACT: Jordan S. Pober Yale University School of Medicine, 295 Congress Ave, New Haven, CT 06510, USA Phone: 203-737-2292; Fax: 203-737-2293; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/21767.pdf

ACCOMPANYING COMMENTARY: The link between IFN-g and allograft arteriopathy: is the answer NO?

Andrew H. Lichtman
Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA Phone: 617-525-4335; Fax: 617-525-4333; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/22927.pdf

A Niche for Kidney Stem Cells

TITLE: The renal papilla is a niche for adult kidney stem cells

Juan A. Oliver
Columbia University, 630 West 168th St, New York, NY 10032, USA
Phone: 212-305-6938; Fax: 212-305-3475; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/20921.pdf

Plant Sterols Disrupt Cholesterol

TITLE: Disruption of cholesterol homeostasis by plant sterols

Helen H. Hobbs
University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA
Phone: 214-648-6724; Fax: 214-648-7539; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/22186.pdf

TKO PKC-q Protects from Insulin Resistance

TITLE: PKC-q knockout mice are protected from fat-induced insulin resistance

Jason K. Kim
Yale University School of Medicine, 300 Cedar St, New Haven, Connecticut 06520, USA
Phone: 203-785-6716; Fax: 203-785-6753; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/22230.pdf

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