One thymus, two thymi...

It's tiny, powerful and, until now, overlooked. Researchers have found that some mice contain not one, but two and possibly more copies of the thymus (Science; doi:10.1126/science.1123497).

This organ regulates the development of T cells and is often removed to study immune responses in the absence of new T cell production. The new findings could complicate the interpretation of such studies.

The thymus—the traditional one—is located close to the heart, and contains about 100 million thymocytes, which eventually leave the thymus as mature T cells. The newly discovered organ is about the size of a small lymph node. Grzegorz Terszowski et al. found that it is lodged in the neck, contains about 600-fold fewer thymocytes and supports normal T-cell development. The tiny thymus could also substitute for the conventional one in genetically athymic mice.

Thymectomized mice are used to study T cell tolerance to antigens in the context of organ transplantation and autoimmunity. Previously, residual T-cell activity after neonatal thymectomy has been attributed to incomplete removal of the organ or export of T cells from the thymus before birth. Now the source of such T cells and the contribution of the second thymus will need to be considered.–AF

Taking down trypanosomes

An analysis of the proteins in the parasite that causes African sleeping sickness has revealed a weak flank. In order to survive in the bloodstream, Trypanosoma brucei requires components of the flagellum (Nature 440, 224–227).

Credit: Samantha Griffiths and Keith Gull

Richard Broadhead and colleagues undertook a detailed analysis of the proteome of the structure. They next ablated various proteins in the flagellum using RNA interference. Ablation of many of these proteins led to failure of cytokinesis in the bloodstream form of the parasite; instead of dividing, the parasites became distorted and died. Numerous flagellar proteins appear to be specific to trypanosomes, suggesting they could be appropriate drug targets. African sleeping sickness is fatal and afflicts an estimated 300,000 to 500,000 people in sub-Saharan Africa.–CS

Put on the pressure

The famed biological regulator, transforming growth factor (TGF)-β, interacts with the a protein in the blood vessel wall to help regulate blood pressure, according to studies in mice by Zacchigna and Vecchione et al. (Cell 124, 929–942).

The researchers found that the vessel protein, the extracellular matrix component Emilin1, is a specific antagonist of TGF-β ligands. Emilin1 also interacts with an immature form of TGF-β and prevents processing of this form into mature TGF-β. TGF-β is known to be involved in the development and physiology of blood vessels, and its activity results in smaller vessel diameter, leading to high blood pressure. The authors propose that Emilin1 restricts the availability of TGF-β in blood vessels.–JB

Turn off the channel

A rare form of epilepsy may be caused by defects in a protein that controls potassium channel closing during neuron firing, suggest Uwe Schulte et al. in the 2 March Neuron (49, 697–706).

When voltage-gated potassium channels are opened during neuronal activation, they help to repolarize the membrane, blunting the firing in that neuron. For the neuron to stop firing, the channels need to remain open until the membrane polarity comes back to baseline. But if the channels close too quickly, the neuron will fire for too long, overactivating nearby neurons. If this happens in enough neurons, seizures may occur.

The researchers examined Lgi1 (leucine-rich glioma inactivated gene 1), a gene of previously unknown function in the nervous system that is mutated in autosomal dominant temporal lobe epilepsy. They found that Lgi1 protein bound to the voltage-gated potassium channel complex in the nervous system. They then expressed Lgi1 with the channel in Xenopus oocytes and recorded potassium currents from these cells. The channels closed slowly in cells expressing wild-type Lgi1—and much more quickly in cells expressing mutant Lgi1 protein.

Although the effect of these Lgi1 mutations on neuronal activity was not examined, these data suggest that mutations in Lgi1 may lead to prolonged neuronal activity in neurons and to epilepsy.–EC

Egregious eosinophils

An underlying defect in an emerging disorder with symptoms similar to acid reflux disease is now revealed (J. Clin. Invest. 116, 536–547).

People with eosinophilic esophagitis (EE) suffer from esophageal inflammation resulting from high levels of eosinophils, a white blood cell that helps fight off infection. Symptoms include chest pain, heartburn, difficulty swallowing and vomiting.

Carine Blanchard et al. performed gene profiling of inflamed esophageal tissue from these individuals and found that EE has a gene signature distinct from that of related esophageal disease. In their profile of EE, the gene encoding eotaxin-3 was the most overexpressed, by an impressive 50-fold. Eotaxin-3 acts as an attractant for eosinophils, so it's easy to see how it might be involved in the development of EE. The researchers supported this view by finding a high frequency of a polymorphism in the eotaxin-3 gene in individuals with EE and showing that mice lacking a receptor for eotaxins, CCR3, were protected from experimental EE.–MB

From guide to assassin

A new route to neuron death during stroke has been identified (J. Neurosci. 26, 2241–2249).

Collapsin response mediator proteins (CMRPs) are best known as mediators of axon guidance—but some groups have suggested that they regulate cell death. Sheng Hou et al. find that CMRP-3 seems to take on this more sinister role during stroke.

They report that CRMP-3 is cleaved by calpain, a protease activated during stroke. The CRMP-3 cleavage product enters the nucleus of neurons after stroke, where it seems to promote cell death. In cell culture experiments, the toxic effect of the CRMP-3 fragment was blocked by calpain inhibitors, drugs known to be neuroprotective in stroke. Downregulation of CRMP-3 expression blocked neuron death induced by glutamate toxicity in culture, but whether in vivo CRMP-3 blockade decreases brain injury after stroke remains to be seen.–EC

Written by Michael Basson, Jasmine Bhatia, Eva Chmielnicki, Alison Farrell and Charlotte Schubert