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JCI online early table of contents: Feb. 15, 2010

EDITOR'S PICK: Immune system turns on the body in narcolepsy

Individuals with the sleep disorder narcolepsy suffer with excessive daytime sleepiness and attacks of muscle paralysis triggered by strong emotions (a condition known as cataplexy). It is thought that narcolepsy is an autoimmune disorder that is, it is caused by the individual's immune system attacking certain cells in the body but this has not yet been proven definitively. However, Mehdi Tafti and colleagues, at the University of Lausanne, Switzerland, have now identified autoantibodies (immune molecules that target a natural protein in the body rather than a protein from an infectious agent) that target the natural protein Trib2 in narcolepsy patients with cataplexy, suggesting that narcolepsy is indeed an autoimmune disorder.

TITLE: Elevated Tribbles homolog 2specific antibody levels in narcolepsy patients


Mehdi Tafti
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
Phone: 4121.692.3971; Fax: 4121.692.3965; E-mail:

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EDITOR'S PICK: New therapeutic target for most common solid cancer in childhood?

A team of researchers, led by Patrick Mehlen, at Universit de Lyon, France, has identified the protein NT-3 and the cell-surface molecule to which it binds (TrkC) as potential therapeutic targets for the treatment of neuroblastoma the most frequent solid tumor in young children by studying human neuroblastoma cells in vitro and after xenotransplantation into mice and chicks.

In the study, NT-3 was found to be expressed at increased levels in aggressive human neuroblastomas and to block the ability of TrkC to induce tumor cell death by a process known as apoptosis. In vitro analysis of human neuroblastoma cell lines indicated that both decreasing NT-3 expression and culturing in the presence of an antibody that blocked NT-3 binding to TrkC triggered the cells to undergo apoptosis. More importantly, blocking the NT-3/TrkC interaction inhibited tumor growth and metastasis in both a chick and a mouse xenograft model of neuroblastoma. The authors therefore suggest that disrupting the NT-3/TrkC interaction might provide a new approach to treating neuroblastoma, a form of cancer for which treatment options are currently limited.

TITLE: Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis


Patrick Mehlen
CNRS UMR5238, Universit de Lyon, Lyon, France.
Phone:; Fax:; E-mail:

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DEVELOPMENT: Deciphering the role of the protein RET in development

Several diseases and developmental defects, including Hirschsprung disease and congenital anomalies of kidneys or urinary tract (CAKUT) syndrome, are caused by mutations in the RET gene. It is not clear, however, how RET gene mutations lead to such a range of diseases, which can occur in isolation or combination. Insight into this issue has now been provided by Sanjay Jain and colleagues, at Washington University School of Medicine, St. Louis, through their analysis of ten strains of RET mutant mice. Specifically, it was determined that different RET-stimulated signaling pathways control the development of the genitourinary system and the enteric and autonomic nervous systems. This conclusion suggests that an individual's disease symptoms are determined by which signaling pathways are disrupted by the RET gene mutation that the individual carries.

TITLE: Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice


Sanjay Jain
Washington University School of Medicine, St. Louis, MO, USA.
Phone: 314.454.8728; Fax: 314.454.7735; E-mail:

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VASCULAR BIOLOGY: Inflammation contributes to blood vessel disease in neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is an inherited tumor disorder caused by mutations in the NF1 gene. Individuals with NF1 have any one of a number of clinical symptoms, including learning difficulties, eye problems, and epilepsy. They also often develop blood vessel disease that can result in blood vessels becoming blocked, although how this symptom of NF1 develops has not been determined. But now, by studying mice that model NF1 and humans with NF1, David Ingram Jr and colleagues, at Indiana University School of Medicine, Indianapolis, have generated genetic and cellular evidence that chronic inflammation contributes to the development of blood vessel disease in patients with NF1. The authors therefore suggest that future studies should focus on harnessing this information to develop potential new avenues for therapeutic and diagnostic purposes.

TITLE: Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans


David A. Ingram Jr.
Indiana University School of Medicine, Indianapolis, IN, USA.
Phone: 317.278.8245; Fax: 317.274.8679; E-mail:

NEPHROLOGY: Role for the protein Sat1 in kidney stones and liver toxicity

A team of researchers, at the University of Queensland, Australia, has studied the function of the protein Sat1 in mice and determined that it is likely to have an important role in acetaminophen-induced liver toxicity (the most common cause of acute liver failure in the Western world) and urolithiasis (a condition in which stones are present in the urinary system, including the kidneys and bladder).

Kidney and urinary stones and liver toxicity are linked to alterations in oxalate and sulfate homeostasis, respectively. The team, led by Daniel Markovich, generated mice lacking Sat1, a mediator of oxalate and sulfate transport that is localized to the kidney, liver, and intestine. Sat1-deficient mice excreted excess amounts of oxalate in their urine (a common symptom in individuals with calcium oxalate kidney stones) and had calcium oxalate stones in their kidney tubules and bladder. These mice also excreted excess amounts of sulfate in their urine and exhibited enhanced acetaminophen-induced liver toxicity. The authors therefore conclude that Sat1 maintains appropriate levels of oxalate and sulfate and may be critical to the development of calcium oxalate kidney and urinary stones and acetaminophen-induced liver toxicity.

TITLE: Urolithiasis and hepatotoxicity are linked to the anion transporter Sat1 in mice


Daniel Markovich
University of Queensland, St. Lucia, Queensland, Australia.
Phone: 61.7.3365.1400; Fax: 61.7.3365.1766; E-mail:

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METABOLIC DISEASE: How the protein WFS1 stops pancreatic beta cells stressing out

Individuals with the inherited disorder Wolfram syndrome develop a form of diabetes known as insulin-dependent diabetes mellitus, which is caused by loss of cells in the pancreas that produce the hormone insulin (beta cells), and suffer from neurological dysfunctions. One form of Wolfram syndrome is caused by mutations in the WFS1 gene, which produces the protein WFS1. Previous studies have shown that the normal function of WFS1 is to protect against a cellular process known as ER stress, but exactly how it does this was not known. However, a team of researchers, led by Fumihiko Urano, at the University of Massachusetts Medical School, Worcester, has now identified the signaling pathway by which WFS1 negatively regulates ER stress. Importantly, this signaling pathway was dysregulated in pancreatic beta cells from mice lacking WFS1 and immune cells from patients with Wolfram syndrome, leading the authors to conclude that unresolved ER stress in the pancreatic beta cells of individuals with Wolfram syndrome leads to their loss and the development of insulin-dependent diabetes mellitus.

TITLE: Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells


Fumihiko Urano
University of Massachusetts Medical School, Worcester, MA, USA.
Phone: 508.856.6012; Fax: 508.856.4650; E-mail:

METABOLIC DISEASE: Two proteins with opposing roles in regulating energy balance

A team of researchers, led by Kendra Bence, at the University of Pennsylvania, Philadelphia, has identified two proteins with opposing roles in the regulation of energy balance by nerve cells in the brain and spinal cord of mice known as POMC neurons.

In the study, mice lacking the protein PTP1B only in POMC neurons (POMC-Ptp1b/ mice) had decreased fat content and expended more energy than normal mice. By contrast, mice lacking the protein SHP2 only in POMC neurons (POMC-Shp2/ mice) had increased fat content and expended less energy than normal mice. Underlying these data was the fact that POMC-Ptp1b/ mice were able to control glucose levels in their blood easily, whereas POMC-Shp2/ mice were not. These data indicate that PTP1B and SHP2 have reciprocal roles in POMC-neuron regulation of energy balance, at least in mice.

TITLE: PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice


Kendra K. Bence
University of Pennsylvania, Philadelphia, PA, USA.
Phone: 215.746.2998; Fax: 215.573.5186; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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