Volume 17 Issue 11, November 2011

The International Mouse Phenotyping Consortium (IMPC), plans to document disease-related phenotypes for each generated mouse strain including metabolic, neurological and behavioral data. Hannah Waters spoke with Steve Brown, chairman of the IMPC and director of the UK Medical Research Council’s Mammalian Genetics Unit in Harwell, to learn more about the project.

Two recently discovered genes involved in ALS could reveal the pathways that are central to the neurodegeneration caused by the disease. But as some researchers storm ahead suggesting treatments targeting these genes, others are questioning how relevant the reports are for nonheritable forms of the disease. Virginia Hughes investigates why the new findings seem to have struck a nerve in the ALS community.

A burst of research into the genetics of autism has given scientists insight into the basis for the disorder. Now, some companies aim to capitalize on these findings by developing DNA screens that might one day provide a diagnosis at birth. Hannah Waters examines the genetic tests and explores what parents—and their autistic children—have to gain.

Ground-breaking science in the area of cannabinoid signaling holds great promise for new drug development, but an unintended consequence of this research has led to the emergence of an onslaught of deadly 'legal highs'. Providing public health scientists with access to laboratory resources designed to investigate emerging chemicals of concern is crucial for timely, sound evaluation of products that pose major threats to public health.

Increasing rates of obesity and obesity-associated type 2 diabetes are threatening to reverse recent gains in reducing the rates of cardiovascular and thrombotic disease. A new study in obese mice shows that tissue factor, the principal initiator of coagulation, is also promoting the development of insulin resistance and obesity (pages 1490–1497).

The identification of a new mode of cell-cell communication mediated by semaphorin 4D (Sema4D) and Plexin-B1 has added another level to the regulatory balance between bone formation and resorption (pages 1473–1480). This study also highlights Sema4D as a potential target for the development of new therapeutics for osteoporosis and other bone disorders associated with increased resorption.

Although erythropoietin (Epo) is commonly used as a therapy for anemia, recent studies have suggested that Epo therapy is associated with adverse outcomes. A new study shows that polymeric IgA1 positively regulates erythropoiesis through binding to transferrin receptor 1 (Tfr1), suggesting new therapeutic routes for anemia (pages 1456–1465).

A new study suggests that regulation of the serum- and glucocorticoid-regulated kinase (SGK1) is important for ensuring uterine receptivity and maintenance of pregnancy (pages 1509–1513). Additional work will be required to determine whether SGK1 could be potentially targeted to treat infertility and prevent miscarriage and whether it can be used as a biomarker.

The complexity of the brain adds another level of difficulty to our understanding of how the brain develops, matures and functions. Both structural and molecular components define brain functional connectivity, and its alteration may result in developmental, behavioral and social deficits. Uncovering the roots and mechanisms behind neurodevelopmental disorders, such as fragile X syndrome or autism, is the goal of several lines of research. Despite the challenges associated with studying these diseases, new advances are linking pathological genetic changes with mechanisms in the brain. In Bench to Bedside, Guoping Feng and Jonathan Ting peruse a study that uncovers how fragile X syndrome–causing gene mutations unleash a translation break that finally leads to overexpression of synaptic proteins that alter the proper transmission of signals at the synapse. Furthermore, changes in the brain during the development of a person can also provide information about when and where the diseased brain loses functional connectivity. In Bedside to Bench, Jeffrey Neul proposes that studying the functional networks in people with autism and other neurodevelopmental disorders, and correlating changes with functional connectivity in animal models of these diseases, will uncover the mechanisms of normal and abnormal development and suggest possible treatment strategies.

Spinocerebellar ataxia 1 is a neurodegenerative disease caused by a CAG trinucleotide expansion in the ATXN1 gene encoding the protein ataxin-1. Puneet Opal and his colleagues find that ataxin-1 represses the expression of the angiogenic and neurotrophic factor vascular endothelial growth factor (VEGF) and that VEGF levels are decreased in animals with motor impairment. Overexpression or infusion of VEGF improves motor performance and pathology, suggesting VEGF may have therapeutic potential in this disease.

Identification of the mechanisms that drive the transition from acute to chronic pain could lead to new treatments. Now, Zhizhong Pan and colleagues demonstrate that chronic pain causes epigenetic downregulation of GAD65 and results in inhibitory neurotransmission deficits in the brainstem of rats.

Séverine Coulon et al. identify a new mechanism regulating red blood cell production through transferrin receptor engagement. By binding this receptor on erythroblasts, the polymeric form of immunoglobin A1 (pIgA1) or iron-loaded transferrin acts in conjunction with erythropoietin to promote erythroblast maturation. Administration of either pIgA1 or iron-loaded transferrin accelerated recovery from anemia in mice, suggesting that these findings may have therapeutic implications.

Ron Evans and his colleagues have shown that excess thyroid hormone receptor signaling during embryonic development in mice impairs the differentiation of type I pneumocytes, a key lung cell type needed for proper gas exchange. They also show that treatment with antithyroid drugs during this stage of development rescues the defect in lung maturation, suggesting a possible therapy for some children born with respiratory distress syndrome.

The holy grail in the bone field is the identification of a pharmacological compound that promotes bone growth during osteoporosis. Hiroshi Takayanagi and his colleagues take a step forward in that direction by showing that osteoclast-mediated expression of semaphorin D inhibits osteoblast differentiation and that, by inhibiting this pathway with a blocking antibody, they could prevent bone loss in a mouse model of osteoporosis.

Helga Ellingsgaard et al. show that secretion of interleukin-6 by muscle in response to exercise, or injection of recombinant protein, increases the expression of the incretin GLP-1 by both intestinal cells and by pancreatic alpha cells, thus potentiating insulin release and improving glycemic control. These results identify a new endocrine loop linking energy demands to homeostatic control while also suggesting further targets for type 2 diabetes therapy.

Fahumiya Samad and her colleagues have shown that the serine protease tissue factor, a key regulator of coagulation, has a role in obesity and metabolic disease. They find that tissue factor signaling in adipocytes promotes obesity, whereas its signaling in adipose tissue macrophages promotes local inflammation and insulin resistance.

Ovarian tumors preferentially metastasize to the omentum, a peritoneal fat layer. This report proposes that the reasons for this predilection stem from the growth advantage conferred by adipocytes on ovarian cancer cells. Adipocytes seem to promote homing of cancer cells through adipokine secretion, and direct contact of the two cell types promotes metabolic changes that result in lipid transfer from adipocytes to tumor cells. Environmental-driven metabolic adaptations could be exploited to target omental metastasis.

The authors find that cell-intrinsic activation of Hedgehog signaling without genetic alterations is a contributing feature to the progression and chemotherapy resistance of small-cell lung carcinoma, and that Hedgehog inhibition can prevent lung cancer growth and recurrence.

Jan Brosens and his colleagues have found that deregulation of a single kinase—SGK1, a kinase involved in fluid balance—in two distinct cellular compartments of the endometrium is linked to two different forms of reproductive failure in humans. Using gain- and loss-of-function approaches in mice, the group confirmed the importance of these expression changes in such pathologies.

By implementing the conditions for orthotopic implantation of different types of human breast tumors, the authors have created a publicly available bank of new mouse models that more faithfully recreate individual tumor properties and provide individualized information about tumor behavior and prognosis.

Vascular dysfunction can cause or contribute to many types of pathology, from hypertension to myocardial infarction to cancer. This series of reviews—inspired by the conference "Vascular Disease 2011: From Bench to Bedside", event cosponsored by the UCSD Clinical and Translational Research Institute and Nature Medicine—highlights new mechanistic findings across a broad spectrum of vascular diseases that may lead to new and innovative treatments.